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UNDERSTANDING FAITH, THE IMMUNE SYSTEM & DISEASE
Pathogen
A pathogen, an infectious agent, or more commonly germ, is a biological agent that causes disease to its host.
There are several substrates and pathways whereby pathogens can invade a host; the principal pathways have
different episodic time frames, but soil contamination has the longest or most persistent potential for harboring a
pathogen.
The body contains many natural orders of defense against some of the common pathogens (such as Pneumocystis) in
the form of the human immune system and by some "helpful" bacteria present in the human body's normal flora.
However, if the immune system or "good" bacteria is damaged in any way (such as by chemotherapy, human
immunodeficiency virus (HIV), or antibiotics being taken to kill other pathogens), pathogenic bacteria that were being
held at bay can proliferate and cause harm to the host. Such cases are called opportunistic infection.
Some pathogens (such as the bacterium Yersinia pestis, which may have caused the Black Plague, the Variola virus,
and the Malaria protozoa) have been responsible for massive numbers of casualties and have had numerous effects on
afflicted groups. Of particular note in modern times is HIV, which is known to have infected several million humans
globally, along with the Influenza virus. Today, while many medical advances have been made to safeguard against
infection by pathogens, through the use of vaccination, antibiotics, and fungicide, pathogens continue to threaten
human life. Social advances such as food safety, hygiene, and water treatment have reduced the threat from some
pathogens.
Not all pathogens are negative. In entomology, pathogens are one of the "Three P's" (predators, pathogens, and
parasitoids) that serve as natural or introduced biological controls to suppress arthropod pest populations.
Below is a list of different types of notable pathogens as categorized by their structural characteristics, and some of
their known and predicted effects on infected host (person).
Types of pathogen
Viral
Pathogenic viruses are mainly those of the families of: Adenoviridae, Picornaviridae, Herpesviridae, Hepadnaviridae,
Flaviviridae, Retroviridae, Orthomyxoviridae, Paramyxoviridae, Papovaviridae, Polyomavirus, Rhabdoviridae,
Togaviridae. Some notable pathogenic viruses cause: smallpox, influenza, mumps, measles, chickenpox, ebola, and
rubella. Viruses typically range between 20-300 nanometers in length.
Bacterial
Although the vast majority of bacteria are harmless or beneficial, a few pathogenic bacteria can cause infectious
diseases. The most common bacterial disease is tuberculosis, caused by the bacterium Mycobacterium tuberculosis,
which affects about 2 million people mostly in sub-Saharan Africa. Pathogenic bacteria contribute to other globally
important diseases, such as pneumonia, which can be caused by bacteria such as Streptococcus and Pseudomonas,
and food borne illnesses, which can be caused by bacteria such as Shigella, Campylobacter and Salmonella. Pathogenic
bacteria also cause infections such as tetanus, typhoid fever, diphtheria, syphilis and leprosy. Bacteria can often be
killed by antibiotics. They typically range between 1-5 micrometers in length.
Fungal
Fungi comprise a eukaryotic kingdom of microbes that are usually saprophytes but can cause diseases in humans,
animals and plants. Fungi are the most common cause of diseases in crops and other plants. Life threatening fungal
infections in humans most often occur in immuno-compromised patients or vulnerable people with a weakened
immune system, although fungi are common problems in the immuno-competent population as the causative agents of
skin, nail or yeast infections. Most antibiotics that function on bacterial pathogens cannot be used to treat fungal
infections due to the fact that fungi and their hosts both have eukaryotic cells. Most clinical fungicides belong to the
azole group. The typical fungal spore size is 1-40 micrometer in length.
Other parasites
Some eukaryotic organisms, such as protists and helminths, cause disease. One of the best known diseases caused by
protists in the genus Plasmodium is malaria.
Prionic
Prions are infectious pathogens that do not contain nucleic acids. Protein malformations caused by prion infections are
implicated in scrapie, bovine spongiform encephalopathy (mad cow disease) and Creutzfeldt–Jakob disease.
Potency
One hypothesis regarding pathogens states that the longer a pathogen can survive outside of the body, the more
dangerous it can be to a potential host. For example, the smallpox virus (variola virus) can survive outside the human
body for approximately 885 days. It is also one of the most deadly pathogenic viruses, as it kills between 20-50% of
the people it infects. The tuberculosis bacterium kills 1 in 5 of the people it infects, but only survives 244 days outside
of its host. However, research into the basis of the ability of pathogens to cause disease provides evidence from
multiple and diverse species of the existence of pathogenicity or virulence factors, encoded within the pathogens'
genetic material, that facilitate microbes to cause disease.
In countries that have higher sanitation standards, pathogens cannot survive for as long outside of the human. This is
seen as encouragement to mutations to the pathogen which would make it less deadly, as such mutations would allow
the pathogen to survive in the host for longer periods of time.
Transmission
One of the primary pathways by which food or water become contaminated is from the release of untreated sewage
into a drinking water supply or onto cropland, with the result that people who eat or drink contaminated sources
become infected. In developing countries most sewage is discharged into the environment or on cropland as of 12
August 1985; even in developed countries there are periodic system failures resulting in a sanitary sewer overflow.
Examples of pathogens
Major human pathogens
 Mycobacterium tuberculosis — the causative agent of most cases of tuberculosis
 Mycobacterium leprae — the bacterium that causes leprosy (Hansen's disease)
 Yersinia pestis — pneumonic, septicemic, and the notorious bubonic plagues (aka "Black Death")
 Rickettsia prowazekii — the etiologic agent of typhus fever
 Bartonella spp.

Spanish influenza virus
Immune system
A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange).
An immune system is a system of biological structures and processes within an organism that protects against
disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to
parasitic worms, and needs to distinguish them from the organism's own healthy cells and tissues in order to function
properly. Detection is complicated as pathogens can evolve rapidly, producing adaptations that avoid the immune
system and allow the pathogens to successfully infect their hosts.
To survive this challenge, multiple mechanisms evolved that recognize and neutralize pathogens. Even simple
unicellular organisms such as bacteria possess enzyme systems that protect against viral infections. Other basic
immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants and
insects. These mechanisms include antimicrobial peptides called defensins, phagocytosis, and the complement system.
Jawed vertebrates, including humans, have even more sophisticated defense mechanisms. The typical vertebrate
immune system consists of many types of proteins, cells, organs, and tissues that interact in an elaborate and dynamic
network. As part of this more complex immune response, the human immune system adapts over time to recognize
specific pathogens more efficiently. This adaptation process is referred to as "adaptive immunity" or "acquired
immunity" and creates immunological memory. Immunological memory created from a primary response to a specific
pathogen, provides an enhanced response to secondary encounters with that same, specific pathogen. This process of
acquired immunity is the basis of vaccination.
Disorders in the immune system can result in disease. Immunodeficiency occurs when the immune system is less
active than normal, resulting in recurring and life-threatening infections. Immunodeficiency can either be the result of
a genetic disease, such as severe combined immunodeficiency, or be produced by pharmaceuticals or an infection,
such as the acquired immune deficiency syndrome (AIDS) that is caused by the retrovirus HIV. In contrast,
autoimmune diseases result from a hyperactive immune system attacking normal tissues as if they were foreign
organisms. Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus type
1, and lupus erythematosus. Immunology covers the study of all aspects of the immune system, having significant
relevance to health and diseases. Further investigation in this field is expected to play a serious role in promotion of
health and treatment of diseases.
Layered defense
The immune system protects organisms from infection with layered defenses of increasing specificity. In simple terms,
physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches
these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems
are found in all plants and animals. If pathogens successfully evade the innate response, vertebrates possess a third
layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system
adapts its response during an infection to improve its recognition of the pathogen. This improved response is then
retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive
immune system to mount faster and stronger attacks each time this pathogen is encountered.
Components of the immune system
Innate immune system
Adaptive immune system
Response is non-specific
Pathogen and antigen specific response
Exposure leads to immediate maximal response Lag time between exposure and maximal response
Cell-mediated and humoral components
Cell-mediated and humoral components
No immunological memory
Exposure leads to immunological memory
Found in nearly all forms of life
Found only in jawed vertebrates
Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and nonself molecules. In immunology, self molecules are those components of an organism's body that can be distinguished
from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign
molecules. One class of non-self molecules are called antigens (short for antibody generators) and are defined as
substances that bind to specific immune receptors and elicit an immune response.
Surface barriers
Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy
cuticle of many leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin
are examples of the mechanical barriers that are the first line of defense against infection. However, as organisms
cannot be completely sealed against their environments, other systems act to protect body openings such as the
lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and
other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens,
while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms.
Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as
the β-defensins. Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also
antibacterials. Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic,
while semen contains defensins and zinc to kill pathogens. In the stomach, gastric acid and proteases serve as
powerful chemical defenses against ingested pathogens.
Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with
pathogenic bacteria for food and space and, in some cases, by changing the conditions in their environment, such as
pH or available iron. This reduces the probability that pathogens will be able to reach sufficient numbers to cause
illness. However, since most antibiotics non-specifically target bacteria and do not affect fungi, oral antibiotics can lead
to an “overgrowth” of fungi and cause conditions such as a vaginal candidiasis (a yeast infection). There is good
evidence that re-introduction of probiotic flora, such as pure
cultures of the lactobacilli normally found in unpasteurized yoghurt, helps restore a healthy balance of microbial
populations in intestinal infections in children and encouraging preliminary data in studies on bacterial gastroenteritis,
inflammatory bowel diseases, urinary tract infection and post-surgical infections.
Innate
Microorganisms or toxins that successfully enter an organism will encounter the cells and mechanisms of the innate
immune system. The innate response is usually triggered when microbes are identified by pattern recognition
receptors, which recognize components that are conserved among broad groups of microorganisms, or when
damaged, injured or stressed cells send out alarm signals, many of which (but not all) are recognized by the same
receptors as those that recognize pathogens.[18] Innate immune defenses are non-specific, meaning these systems
respond to pathogens in a generic way.[5] This system does not confer long-lasting immunity against a pathogen. The
innate immune system is the dominant system of host defense in most organisms.
Humoral and chemical barriers
Inflammation
Inflammation is one of the first responses of the immune system to infection. The symptoms of inflammation are
redness and swelling, which are caused by increased blood flow into a tissue. Inflammation is produced by eicosanoids
and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever
and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells
(leukocytes). Common cytokines include interleukins that are responsible for communication between white blood
cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein
synthesis in the host cell. Growth factors and cytotoxic factors may also be released. These cytokines and other
chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the
removal of pathogens.
Complement system
The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20
different proteins and is named for its ability to “complement” the killing of pathogens by antibodies. Complement is
the major humoral component of the innate immune response. Many species have complement systems, including
non-mammals like plants, fish, and some invertebrates.
In humans, this response is activated by complement binding to antibodies that have attached to these microbes or
the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a
rapid killing response. The speed of the response is a result of signal amplification that occurs following sequential
proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to
the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This
produces a catalytic cascade that amplifies the initial signal by controlled positive feedback. The cascade results in the
production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a
pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their
plasma membrane.
Cellular barriers
A scanning electron microscope image of normal circulating human blood. One can see red blood cells, several knobby
white blood cells including lymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets.
Leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate
immune system. The innate leukocytes include the phagocytes (macrophages, neutrophils, and dendritic cells), mast
cells, eosinophils, basophils, and natural killer cells. These cells identify and eliminate pathogens, either by attacking
larger pathogens through contact or by engulfing and then killing microorganisms. Innate cells are also important
mediators in the activation of the adaptive immune system.
Phagocytosis is an important feature of cellular innate immunity performed by cells called 'phagocytes' that engulf, or
eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific
locations by cytokines. Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular
vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a
phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that
releases free radicals into the phagolysosome. Phagocytosis evolved as a means of acquiring nutrients, but this role
was extended in phagocytes to include engulfment of pathogens as a defense mechanism. Phagocytosis probably
represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate
animals.
Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens.
Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, normally
representing 50% to 60% of the total circulating leukocytes. During the acute phase of inflammation, particularly as a
result of bacterial infection, neutrophils migrate toward the site of inflammation in a process called chemotaxis, and
are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues
and produce a wide array of chemicals including enzymes, complement proteins, and regulatory factors such as
interleukin 1. Macrophages also act as scavengers, ridding the body of worn-out cells and other debris, and as antigenpresenting cells that activate the adaptive immune system.
Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment; therefore, they are
located mainly in the skin, nose, lungs, stomach, and intestines. They are named for their resemblance to neuronal
dendrites, as both have many spine-like projections, but dendritic cells are in no way connected to the nervous
system. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as
they present antigen to T cells, one of the key cell types of the adaptive immune system.
Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response. They are
most often associated with allergy and anaphylaxis. Basophils and eosinophils are related to neutrophils. They secrete
chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as
asthma. Natural killer (NK cells) cells are leukocytes that attack and destroy tumor cells, or cells that have been
infected by viruses.
Adaptive
The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as
immunological memory, where each pathogen is "remembered" by a signature antigen. The adaptive immune
response is antigen-specific and requires the recognition of specific “non-self” antigens during a process called antigen
presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or
pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells".
Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.
Lymphocytes
The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are
the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are
involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response.
Association of a T cell with MHC class I or MHC class II, and antigen (in red)
Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a “non-self” target,
such as a pathogen, only after antigens (small fragments of the pathogen) have been pressed and presented in
combination with a “self” receptor called a major histocompatibility complex (MHC) molecule. There are two major
subtypes of T cells: the killer T cell and the helper T cell. Killer T cells only recognize antigens coupled to Class I MHC
molecules, while helper T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of
antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that
recognize intact antigens that are not bound to MHC receptors.
In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes whole
pathogens without any need for antigen processing. Each lineage of B cell expresses a different antibody, so the
complete set of B cell antigen receptors represent all the antibodies that the body can manufacture.
Killer T cells
Killer T cells directly attack other cells carrying foreign or abnormal antigens on their surfaces.
Killer T cell are a sub-group of T cells that kill cells that are infected with viruses (and other pathogens), or are
otherwise damaged or dysfunctional. As with B cells, each type of T cell recognises a different antigen. Killer T cells
are activated when their T cell receptor (TCR) binds to this specific antigen in a complex with the MHC Class I receptor
of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T cell
then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T
cell contacts such cells, it releases cytotoxins, such as perforin, which form pores in the target cell's plasma
membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease) induces
the target cell to undergo apoptosis. T cell killing of host cells is particularly important in preventing the replication of
viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or
additional activation signals provided by "helper" T cells (see below).
Helper T cells
Function of T helper cells: Antigen presenting cells (APCs) present antigen on their Class II MHC molecules (MHC2).
Helper T cells recognize these, with the help of their expression of CD4 co-receptor (CD4+). The activation of a resting
helper T cell causes it to release cytokines and other stimulatory signals (green arrows) that stimulate the activity of
macrophages, killer T cells and B cells, the latter producing antibodies. The stimulation of B cells and macrophages
succeeds a proliferation of T helper cells.
Helper T cells regulate both the innate and adaptive immune responses and help determine which types of immune
responses the body will make to a particular pathogen. These cells have no cytotoxic activity and do not kill infected
cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these
tasks.
Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. The
MHC:antigen complex is also recognized by the helper cell's CD4 co-receptor, which recruits molecules inside the T cell
(e.g., Lck) that are responsible for the T cell's activation. Helper T cells have a weaker association with the
MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T cell
must be bound by an MHC:antigen in order to activate the helper cell, while killer T cells can be activated by
engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement
with an antigen-presenting cell. The activation of a resting helper T cell causes it to release cytokines that influence
the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of
macrophages and the activity of killer T cells. In addition, helper T cell activation causes an upregulation of molecules
expressed on the T cell's surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals
typically required to activate antibody-producing B cells.
γδ T cells
γδ T cells possess an alternative T cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the
characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells
are not fully understood. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted
Natural Killer T cells, γδ T cells straddle the border between innate and adaptive immunity. [49] On one hand, γδ T cells
are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also
develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as
restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human
Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells
in epithelia will respond to stressed epithelial cells.
An antibody is made up of two heavy chains and two light chains. The unique variable region allows an antibody to
recognize its matching antigen.
B lymphocytes and antibodies
A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. [50] This antigen/antibody
complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then displays these antigenic
peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell,
which releases lymphokines and activates the B cell. As the activated B cell then begins to divide, its offspring (plasma
cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma
and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for
uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins
or by interfering with the receptors that viruses and bacteria use to infect cells.
Alternative adaptive immune system
Although the classical molecules of the adaptive immune system (e.g., antibodies and T cell receptors) exist only in
jawed vertebrates, a distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such
as the lamprey and hagfish. These animals possess a large array of molecules called variable lymphocyte receptors
(VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of
genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same
degree of specificity.
Immunological memory
When B cells and T cells are activated and begin to replicate, some of their offspring will become long-lived memory
cells. Throughout the lifetime of an animal, these memory cells will remember each specific pathogen encountered and
can mount a strong response if the pathogen is detected again. This is "adaptive" because it occurs during the lifetime
of an individual as an adaptation to infection with that pathogen and prepares the immune system for future
challenges. Immunological memory can be in the form of either passive short-term memory or active long-term
memory.
Passive memory
Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of
passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is
transported from mother to baby directly across the placenta, so human babies have high levels of antibodies even at
birth, with the same range of antigen specificities as their mother. Breast milk or colostrum also contains antibodies
that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its
own antibodies. This is passive immunity because the fetus does not actually make any memory cells or antibodies—it
only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In
medicine, protective passive immunity can also be transferred artificially from one individual to another via antibodyrich serum.
The time-course of an immune response begins with the initial pathogen encounter, (or initial vaccination) and leads to
the formation and maintenance of active immunological memory.
Active memory and immunization
Long-term active memory is acquired following infection by activation of B and T cells. Active immunity can also be
generated artificially, through vaccination. The principle behind vaccination (also called immunization) is to introduce
an antigen from a pathogen in order to stimulate the immune system and develop specific immunity against that
particular pathogen without causing disease associated with that organism. This deliberate induction of an immune
response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With
infectious disease remaining one of the leading causes of death in the human population, vaccination represents the
most effective manipulation of the immune system mankind has developed.
Most viral vaccines are based on live attenuated viruses, while many bacterial vaccines are based on acellular
components of micro-organisms, including harmless toxin components. Since many antigens derived from acellular
vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional adjuvants
that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity.
Other mechanisms
It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not
generate lymphocytes or an antibody-based humoral response. Many species, however, utilize mechanisms that
appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the structurally
most simple forms of life, with bacteria using a unique defense mechanism, called the restriction modification system
to protect themselves from viral pathogens, called bacteriophages. Prokaryotes also possess acquired immunity,
through a system that uses CRISPR sequences to retain fragments of the genomes of phage that they have come into
contact with in the past, which allows them to block virus replication through a form of RNA interference.
Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with
pathogens. Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune
response found in all animals and plants, and represent the main form of invertebrate systemic immunity. The
complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA
interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to
viruses.
Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic chemical signals that
are sent through a plant. Individual plant cells respond to molecules associated with pathogens known as Pathogenassociated molecular patterns or PAMPs. When a part of a plant becomes infected, the plant produces a localized
hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the
disease to other parts of the plant. Systemic acquired resistance (SAR) is a type of defensive response used by plants
that renders the entire plant resistant to a particular infectious agent. RNA silencing mechanisms are particularly
important in this systemic response as they can block virus replication.
Physiological regulation
Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex
hormones are known immunostimulators of both adaptive and innate immune responses. Some autoimmune diseases
such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By contrast,
male sex hormones such as testosterone seem to be immunosuppressive. Other hormones appear to regulate the
immune system as well, most notably prolactin, growth hormone and vitamin D. It is conjectured that a progressive
decline in hormone levels with age is partially responsible for weakened immune responses in aging individuals.
Conversely, some hormones are regulated by the immune system, notably thyroid hormone activity.
The immune system is affected by sleep and rest, and sleep deprivation is detrimental to immune function. Complex
feedback loops involving cytokines, such as interleukin-1 and tumor necrosis factor-α produced in response to
infection, appear to also play a role in the regulation of non-rapid eye movement (REM) sleep. Thus the immune
response to infection may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to
REM sleep.
Nutrition and diet
The functioning of the immune system, like most systems in the body, is dependent on proper nutrition. It has been
long known that severe malnutrition leads to immunodeficiency. Overnutrition is also associated with diseases such as
diabetes and obesity, which are known to affect immune function. More moderate malnutrition, as well as certain
specific trace mineral and nutrient deficiencies, can also compromise the immune response.
Specific foods may also affect the immune system; for example, fresh fruits, vegetables, and foods rich in certain fatty
acids may foster a healthy immune system. Likewise, fetal undernourishment can cause a lifelong impairment of the
immune system. In traditional medicine, some herbs are believed to stimulate the immune system, such as echinacea,
licorice, ginseng, astragalus, sage, garlic, elderberry, and hyssop, as well as honey although further research is needed
to understand their mode of action.
Medicinal mushrooms like Shiitake, Lingzhi mushrooms, the Turkey tail mushroom, Agaricus blazei, and Maitake have
shown some evidence of immune system up-regulation in in vitro and in vivo studies, as well as in a limited number of
clinical studies. Research suggests that the compounds in medicinal mushrooms most responsible for up-regulating the
immune system are a diverse collection of polysaccharides, particularly beta-glucans, and to a lesser extent, alphaglucans (such as Active Hexose Correlated Compound isolated from Shiitake). The mechanisms by which beta-glucans
stimulate the immune system is only partially understood. One mechanism by which beta-glucans are thought affect
immune function is through interaction with the complement receptor 3 (CD18), which is expressed on several types of
immune cells. Other receptors–such as Toll-like receptor 2, Dectin-1, lactosylceramide, and scavenger receptors–have
also been identified as being able to receive signals from beta-glucans.
Manipulation in medicine
The immunosuppressive drug dexamethasone
The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and
transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system.
Immunosuppressive drugs are used to control autoimmune disorders or inflammation when excessive tissue damage
occurs, and to prevent transplant rejection after an organ transplant.
Anti-inflammatory drugs are often used to control the effects of inflammation. The glucocorticoids are the most
powerful of these drugs; however, these drugs can have many undesirable side effects (e.g., central obesity,
hyperglycemia, osteoporosis) and their use must be tightly controlled. Therefore, lower doses of anti-inflammatory
drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine.
Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. However, the killing is
indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects.
Immunosuppressive drugs such as ciclosporin prevent T cells from responding to signals correctly by inhibiting signal
transduction pathways.
Larger drugs (>500 Da) can provoke a neutralizing immune response, particularly if the drugs are administered
repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are
typically larger than 6000 Da). In some cases, the drug itself is not immunogenic, but may be co-administered with an
immunogenic compound, as is sometimes the case for Taxol. Computational methods have been developed to predict
the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies,
assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug
treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in
epitope regions than hydrophobic amino acids; however, more recent developments rely on machine learning
techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set. A
publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be
recognizable by B cells. The emerging field of bioinformatics-based studies of immunogenicity is referred to as
immunoinformatics.
Manipulation by pathogens
The success of any pathogen is dependent on its ability to elude host immune responses. Therefore, pathogens have
evolved several methods that allow them to successfully infect a host, while evading detection or destruction by the
immune system. Bacteria often overcome physical barriers by secreting enzymes that digest the barrier — for example,
by using a type II secretion system. Alternatively, using a type III secretion system, they may insert a hollow tube into
the host cell, providing a direct route for proteins to move from the pathogen to the host. These proteins are often
used to shut down host defenses.
An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their
host (also called intracellular pathogenesis). Here, a pathogen spends most of its life-cycle inside host cells, where it is
shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens
include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium
falciparum) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a
protective capsule that prevents lysis by complement. Many pathogens secrete compounds that diminish or misdirect
the host's immune response. Some bacteria form biofilms to protect themselves from the cells and proteins of the
immune system. Such biofilms are present in many successful infections, e.g., the chronic Pseudomonas aeruginosa
and Burkholderia cenocepacia infections characteristic of cystic fibrosis. Other bacteria generate surface proteins that
bind to antibodies, rendering them ineffective; examples include Streptococcus (protein G), Staphylococcus aureus
(protein A), and Peptostreptococcus magnus (protein L).
The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is to
rapidly change non-essential epitopes (amino acids and/or sugars) on the surface of the pathogen, while keeping
essential epitopes concealed. This is called antigenic variation. An example is HIV, which mutates rapidly, so the
proteins on its viral envelope that are essential for entry into its host target cell are constantly changing. These
frequent changes in antigens may explain the failures of vaccines directed at this virus. The parasite Trypanosoma
brucei uses a similar strategy, constantly switching one type of surface protein for another, allowing it to stay one step
ahead of the antibody response. Masking antigens with host molecules is another common strategy for avoiding
detection by the immune system. In HIV, the envelope that covers the viron is formed from the outermost membrane
of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify them as "non-self"
structures.
The Immune System -- An Overview
The immune system is composed of many interdependent cell types that collectively protect the body from bacterial,
parasitic, fungal, viral infections and from the growth of tumor cells. Many of these cell types have specialized
functions. The cells of the immune system can engulf bacteria, kill parasites or tumor cells, or kill viral-infected cells.
Often, these cells depend on the T helper subset for activation signals in the form of secretions formally known as
cytokines, lymphokines, or more specifically interleukins. The purpose of this article is to review the organs, cell types
and interactions between cells of the immune system as a commentary on their importance and interdependence on
the T helper subset. Such an understanding may help comprehend the root of immune deficiencies, and perceive
potential avenues that the immune system can be modulated in the case of specific diseases.
The Organs of the Immune System
Bone Marrow -- All the cells of the immune system are initially derived from the bone marrow. They form through a
process called hematopoiesis. During hematopoiesis, bone marrow-derived stem cells differentiate into either mature
cells of the immune system or into precursors of cells that migrate out of the bone marrow to continue their
maturation elsewhere. The bone marrow produces B cells, natural killer cells, granulocytes and immature thymocytes,
in addition to red blood cells and platelets.
Thymus -- The function of the thymus is to produce mature T cells. Immature thymocytes, also known as
prothymocytes, leave the bone marrow and migrate into the thymus. Through a remarkable maturation process
sometimes referred to as thymic education, T cells that are beneficial to the immune system are spared, while those T
cells that might evoke a detrimental autoimmune response are eliminated. The mature T cells are then released into
the bloodstream.
Spleen -- The spleen is an immunologic filter of the blood. It is made up of B cells, T cells, macrophages, dendritic
cells, natural killer cells and red blood cells. In addition to capturing foreign materials (antigens) from the blood that
passes through the spleen, migratory macrophages and dendritic cells bring antigens to the spleen via the
bloodstream. An immune response is initiated when the macrophage or dendritic cells present the antigen to the
appropriate B or T cells. This organ can be thought of as an immunological conference center. In the spleen, B cells
become activated and produce large amounts of antibody. Also, old red blood cells are destroyed in the spleen.
Lymph Nodes -- The lymph nodes function as an immunologic filter for the bodily fluid known as lymph. Lymph
nodes are found throughout the body. Composed mostly of T cells, B cells, dendritic cells and macrophages, the nodes
drain fluid from most of our tissues. Antigens are filtered out of the lymph in the lymph node before returning the
lymph to the circulation. In a similar fashion as the spleen, the macrophages and dendritic cells that capture antigens
present these foreign materials to T and B cells, consequently initiating an immune response.
The Cells of the Immune System
T-Cells -- T lymphocytes are usually divided into two major subsets that are functionally and phenotypically
(identifiably) different. The T helper subset, also called the CD4+ T cell, is a pertinent coordinator of immune
regulation. The main function of the T helper cell is to augment or potentiate immune responses by the secretion of
specialized
factors
that
activate
other
white
blood
cells
to
fight
off
infection.
Another important type of T cell is called the T killer/suppressor subset or CD8+ T cell. These cells are important in
directly killing certain tumor cells, viral-infected cells and sometimes parasites. The CD8+ T cells are also important in
down-regulation of immune responses. Both types of T cells can be found throughout the body. They often depend on
the secondary lymphoid organs (the lymph nodes and spleen) as sites where activation
occurs, but they are also found in other tissues of the body, most conspicuously the liver, lung, blood, and intestinal
and reproductive tracts.
Natural Killer Cells -- Natural killer cells, often referred to as NK cells, are similar to the killer T cell subset (CD8+ T
cells). They function as effector cells that directly kill certain tumors such as melanomas, lymphomas and viral-infected
cells, most notably herpes and cytomegalovirus-infected cells. NK cells, unlike the CD8+ (killer) T cells, kill their targets
without a prior "conference" in the lymphoid organs. However, NK cells that have been activated by secretions from
CD4+ T cells will kill their tumor or viral-infected targets more effectively.
B Cells -- The major function of B lymphocytes is the production of antibodies in response to foreign proteins of
bacteria, viruses, and tumor cells. Antibodies are specialized proteins that specifically recognize and bind to one
particular protein that specifically recognize and bind to one particular protein. Antibody production and binding to a
foreign substance or antigen, often is critical as a means of signaling other cells to engulf, kill or remove that
substance from the body.
Granulocytes or Polymorphonuclear (PMN) Leukocytes -- Another group of white blood cells is collectively
referred to as granulocytes or polymorphonuclear leukocytes (PMNs). Granulocytes are composed of three cell types
identified as neutrophils, eosinophils and basophils, based on their staining characteristics with certain dyes. These
cells are predominantly important in the removal of bacteria and parasites from the body. They engulf these foreign
bodies and degrade them using their powerful enzymes.
Macrophages -- Macrophages are important in the regulation of immune responses. They are often referred to as
scavengers or antigen-presenting cells (APC) because they pick up and ingest foreign materials and present these
antigens to other cells of the immune system such as T cells and B cells. This is one of the important first steps in the
initiation of an immune response. Stimulated macrophages exhibit increased levels of phagocytosis and are also
secretory.
Dendritic Cells -- Another cell type, addressed only recently, is the dendritic cell. Dendritic cells, which also originate
in the bone marrow, function as antigen presenting cells (APC). In fact, the dendritic cells are more efficient apcs than
macrophages. These cells are usually found in the structural compartment of the lymphoid organs such as the thymus,
lymph nodes and spleen. However, they are also found in the bloodstream and other tissues of the body. It is believed
that they capture antigen or bring it to the lymphoid organs where an immune response is initiated. Unfortunately, one
reason we know so little about dendritic cells is that they are extremely hard to isolate, which is often a prerequisite
for the study of the functional qualities of specific cell types. Of particular issue here is the recent finding that dendritic
cells bind high amount of HIV, and may be a reservoir of virus that is transmitted to CD4+ T cells during an activation
event.
The Immune Response
An immune response to foreign antigen requires the presence of an antigen-presenting cell (APC), (usually either a
macrophage or dendritic cell) in combination with a B cell or T cell. When an APC presents an antigen on its cell
surface to a B cell, the B cell is signalled to proliferate and produce antibodies that specifically bind to that antigen. If
the antibodies bind to antigens on bacteria or parasites it acts as a signal for pmns or macrophages to engulf
(phagocytose) and kill them. Another important function of antibodies is to initiate the "complement destruction
cascade." When antibodies bind to cells or bacteria, serum proteins called complement bind to the immobilized
antibodies and destroy the bacteria by creating holes in them. Antibodies can also signal natural killer cells and
macrophages to kill viral or bacterial-infected cells.
If the APC presents the antigen to T cells, the T cells become activated. Activated T cells proliferate and become
secretory in the case of CD4+ T cells, or, if they are CD8+ T cells, they become activated to kill target cells that
specifically express the antigen presented by the APC. The production of antibodies and the activity of CD8+ killer T
cells are highly regulated by the CD4+ helper T cell subset. The CD4+ T cells provide growth factors or signals to
these cells that signal them to proliferate and function more efficiently. This multitude of interleukins or cytokines that
are produced and secreted by CD4+ T cells are often crucial to ensure the activation of natural killer cells,
macrophages, CD8+ T cells, and PMNs is listed in the chart below.
Red blood cells
The main function of red blood cells, or erythrocytes, is the transport of oxygen from the lungs to body tissues.
Erythrocytes are tiny disk-shaped structures that are hollowed out on either side. Their small size allows them to
squeeze through microscopic blood vessels called capillaries. They number about 5 million per cubic millimeter of
blood; in the entire human body, there are about 25 trillion red blood cells.
Red blood cells are formed in the red bone marrow of certain bones, where they produce a substance called
hemoglobin. Hemoglobin is a protein pigment that contains iron and that gives red blood cells their color. The
hemoglobin in red blood cells combines with oxygen in the lungs, transporting that oxygen to the tissues throughout
the body. It also carries carbon dioxide from the tissues back to the lungs, where some of the carbon dioxide is
exhaled. Each red blood cell lives only about four months. New red blood cells are constantly being produced in the
bone marrow to take the place of old ones.
A single hemoglobin molecule is made of four identical sub-units. Each sub-unit has a heme component, aglobin chain
and an iron atom bound to the heme section. Red blood cells are completely lacking in most other common cellular
parts, such as a nucleus with DNA, or mitochondria.
Oxygen is able to bind to each of the iron atoms, meaning that a single hemoglobin molecule is able to carry up to
four oxygen molecules at its maximum capacity. Interestingly, the structure of hemoglobin makes it such that the
more oxygen that is bound to one of the sub-units, the more other oxygen molecules are attracted to the remaining
iron atoms. This effect is important to the proper functioning of a red blood cell in oxygen transport.
The ability of oxygen to bind to hemoglobin is effected by many factors. The acidity of the blood (pH) is a primary
factor, as is the temperature. Fetal blood has a different ability to bind oxygen (it holds on to the oxygen more tightly).
Other chemicals such as hydrogen sulfide, carbon monoxide, hydrogen sulfide and 2,3bisphosphoglycerate also effect
the ability of hemoglobin to carry oxygen.
Secondary functions
When erythrocytes undergo shear stress in constricted vessels, they release ATP which causes the vessel walls to relax
and dilate so as to promote normal blood flow.
When their hemoglobin molecules are deoxygenated, erythrocytes release S-nitrosothiols which also acts to dilate
vessels, thus directing more blood to areas of the body depleted of oxygen.
It has been recently demonstrated that erythrocytes can also synthesize nitric oxide enzymatically, using L-arginine as
substrate, just like endothelial cells. Exposure of erythrocytes to physiological levels of shear stress activates nitric
oxide synthase and export of nitric oxide, which may contribute to the regulation of vascular tonus.
Erythrocytes can also produce hydrogen sulfide, a signalling gas that acts to relax vessel walls. It is believed that the
cardioprotective effects of garlic are due to erythrocytes converting its sulfur compounds into hydrogen sulfide.
Erythrocytes also play a part in the body's immune response: when lysed by pathogens such as bacteria, their
hemoglobin releases free radicals which break down the pathogen's cell wall and membrane, killing it.
Life cycle
Human erythrocytes are produced through a process named erythropoiesis, developing from committed stem cells to
mature erythrocytes in about 7 days. When matured, these cells live in blood circulation for about 100 to 120 days. At
the end of their lifespan, they become senescent, and are removed from circulation.
Erythropoiesis
Erythropoiesis is the development process in which new erythrocytes are produced, through which each cell matures in
about 7 days. Through this process erythrocytes are continuously produced in the red bone marrow of large bones, at
a rate of about 2 million per second in a healthy adult. (In the embryo, the liver is the main site of red blood cell
production.) The production can be stimulated by the hormone erythropoietin (EPO), synthesised by the kidney. Just
before and after leaving the bone marrow, the developing cells are known as reticulocytes; these comprise about 1%
of circulating red blood cells.
Functional lifetime
This phase lasts about 100–120 days, during which the erythrocytes are continually moving by the blood flow push (in
arteries), pull (in veins) and squeezing through microvessels such as capillaries as they compress against each other in
order to move.
Senescence
The aging erythrocyte undergoes changes in its plasma membrane, making it susceptible to selective recognition by
macrophages and subsequent phagocytosis in the reticuloendothelial system (spleen, liver and bone marrow), thus
removing old and defective cells and continually purging the blood. This process is termed eryptosis, or erythrocyte
programmed cell death. This process normally occurs at the same rate of production by erythropoiesis, balancing the
total circulating red blood cell count. Much of the resulting important breakdown products are recirculated in the body.
The heme constituent of hemoglobin are broken down into Fe3+ and biliverdin. The biliverdin is reduced to bilirubin,
which is released into the plasma and recirculated to the liver bound to albumin. The iron is released into the plasma
to be recirculated by a carrier protein called transferrin. Almost all erythrocytes are removed in this manner from the
circulation before they are old enough to hemolyze. Hemolyzed hemoglobin is bound to a protein in plasma called
haptoglobin which is not excreted by the kidney.
Antibiotics, bacteria and “not” viruses
Antibiotics are medicines that help your body fight bacteria and viruses, either by directly killing the offending bugs or
by weakening them so that your own immune system can fight and kill them more easily. The vast majority of
antibiotics are bacteria fighters; although there are millions of viruses, we only have antibiotics for half-a-dozen or so
of them. Bacteria, on the other hand, are more complex (while viruses must "live" in a "host" (us), bacteria can live
independently) and so are easier to kill.
(A note for the purists: strictly speaking, an "antibiotic" is a bacteria-fighting medicine that is derived from a biological
source (plant, mold, or other bacteria). Since most people use the term "antibiotic" for any anti-infection medicine, we
are doing the same here.)
Antibiotic Resistance
Bacteria (and viruses) aren't particularly intelligent. However, it is possible -- and unfortunately all too common -- for
bacteria and some viruses to "learn" how to survive even with antibiotics around.
There are several ways that bacteria can become resistant. All of them involve changes in the bacteria's genes.
 Bacterial genes mutate (change), just like the genes of larger organisms (including humans) mutate. Some of
these changes happen because of chemical or radiation exposure; some just happen randomly, and no one's
sure quite why. If bacteria with a changed gene is less susceptible to an antibiotic, and that antibiotic is
around, the less susceptible (and more resistant) version of the bacteria is more likely to survive the antibiotic
and continue to multiply. This is particularly likely to happen if the amount of antibiotic around isn't quite
enough to kill all of the bacteria quickly -- as can happen if you don't take enough of the antibiotic to keep its
level in your body high, or if you stop taking the antibiotic too early. This is why when you are prescribed an
antibiotic you MUST take it exactly as prescribed, and for as long as it was prescribed : you may feel better
after only a short time, but you may still have some bacteria left in you -- not enough to make you feel bad,
but enough to come back -- and those bacteria left include the ones that are partly resistant to the antibiotic
already and likely to become more resistant. It's also why an antibiotic should not be given for an illness like a
cold that isn't likely to be bacterial: the antibiotic will kill off susceptible bacteria, leaving bacteria that are
resistant to that antibiotic and which can cause a later infection -- and one that won't respond to the previous
antibiotic.
 Although there are many different species of bacteria, some bacteria can "trade" genes with other bacteria. If
you have a relatively harmless bacteria in you -- say, in your mouth or your intestines (both places are chock
full of bacteria) -- and you've used (or overused or misused) antibiotics some of those harmless bacteria will
become resistant to the antibiotics you've (over-, mis-)used. They can then give the resistance genes they
have developed to other, harmful bacteria.
 There are viruses around that attack bacteria rather than plants, animals, or people. Most of these viruses just
kill the bacteria, but sometimes the viruses can copy genes -- like the antibiotic resistance genes -- from one
kind of bacteria to another.
Human and animal viruses can also develop resistance to antiviral antibiotics, usually through mutation. This isn't a big
issue, since there aren't a lot of antiviral antibiotics. However, antiviral resistance has become a major problem in HIV
(AIDS) therapy, where the virus rapidly becomes resistant to the first-line antivirals such as AZT. Resistance develops
particularly fast in patients who do not take their medicines properly, and in those whose immune systems can't help
clean up after the antibiotics. This is one reason why tuberculosis (which is caused by a bacteria that multiplies very
slowly and that is specifically fought by the part of the immune system that HIV disables) has resurged since the
appearance of AIDS.
Kinds of Antibiotics
There are now so many different antibiotics on the market, it's hard to keep track of them all.
Penicillins and Cephalosporins
In the early 20th century, Alexander Fleming discovered that a mold called Penicillium (the cells are pencil-shaped
when you look at them under a microscope) produces chemicals which kills most of the bacteria nearby. (The mold is
green when it grows in large amounts, and is often found on bread. This, however, does not mean that eating moldy
bread will cure your ear ache -- or anything else. There are other things produced by molds...) He was able to isolate
these chemicals, which are now known as "penicillins". Sometime later, another mold was found which produced a
bacteria-killing chemical, and this chemical's molecule was found to be very similar to the penicillin molecule; this
chemical and its cousins were called "cephalosporins" after the mold it came from. The vast majority of antibiotics are
either penicillins or cephalosporins; chemical changes have been made to the molecules over the years to improve
their bacteria-fighting abilities and to help them overcome breakdown and "immunity" of resistant bacteria.
Most bacterial cells have double layers on their outside. The outermost layer -- the "cell wall" -- is similar to the outer
layer of plant cells, but is missing in human and animal cells. This wall must grow along with the cell, or the growing
cell will eventually become too big for the wall and burst and die. Penicillins and cephalosporins kill bacteria by
messing up the wall-building system. Since we don't have cell walls, and plants have a different wall-building system,
neither we, nor animals, nor plants are affected by the medicine.
There are a very few bacteria that don't have cell walls, either. These bugs are immune to penicillins and
cephalosporins for the same reasons we are. Most bacteria do have cell walls, but many have changed their wallbuilding systems so that penicillins can't interfere, or have come up with ways to break down the medicines before the
medicines can work. When we first started using penicillin in the 40's and 50's, most bacteria could be killed by plain
penicillin. Now, because we have used penicillins and cephalosporins so often (and, in many cases, when we really
shouldn't have), there are many bacteria that can't be killed any more by plain penicillin or even by the "superpenicillins" and "super-cephalosporins".
Penicillins and cephalosporins usually don't cause many problems for a patient. Like all antibiotics, they can cause mild
side effects like diarrhea. Less common side effects include rashes (which may or may not imply a true allergy) and
hives (which usually means you're allergic to the medicine). The rarest -- and scariest -- side effect is "anaphylactic"
allergy, in which your airway swells up when you take a dose of the medicine, sometimes to the point where you can't
breathe. Although the reaction can be treated if you are close to help, the safest thing if you are that allergic to the
medicine is never to take it at all. (In cases where one has an anaphylactic allergy to penicillin or cephalosporins and
must have it to treat an infection, doctors can "desensitize" the person temporarily, using very small doses that are
given frequently and in increasing amounts. That is almost always done in a hospital.)
Macrolides (Erythromycin and its Relatives)
Erythromycin is another antibacterial produced by a mold. There are a couple of new relatives of erythromycin
(azithromycin and clarithromycin) that work the same way, but kill more bugs and have slightly fewer side effects. The
erythromycin-like antibiotics are also known as macrolides.
Erythromycin works by blocking the bacterial cell's machinery for making new proteins. Since proteins both make up
much of the cell's structure and make the enzymes that direct all the cell's chemical reactions, blocking protein
manufacturing makes the cell unable to function. Erythromycin in low doses will stop bacteria from growing and
multiplying, but you need a higher concentration to kill the bacteria. However, if you can stop growth until your
immune system kicks in, that will help you get rid of the infection.
Since all protein making is affected, erythromycin can slow down or kill any bacteria, even those without cell walls.
Because of this, we use the erythromycins for several diseases, including bacterial bronchitis, chlamydia, and whooping
cough, that penicillins and cephalosporins can't touch.
Erythromycin and its cousins don't have anything like the allergy problems we see with the penicillins and
cephalosporins, although there are rare people who have reactions to it. The biggest problem with these medicines is
that they can irritate the stomach. A patient can end up with bleeding stomach ulcers after taking erythromycin; this
irritation seems to happen most often when someone tries to take the medicine on an empty stomach. Always take
erythromycin with food or milk. (The same goes for clarithromycin. Azithromycin doesn't irritate the stomach nearly as
much as the others.) Another problem with erythromycin -- but not with azithromycin -- is that it may cause
enlargement of the pylorus, the muscle that serves as the valve at the outlet of the stomach -- in infants. This
condition is known as pyloric stenosis, and is a surgical emergency if it occurs since nothing can leave the stomach
properly. In the past infants were treated with erythromycin if they developed whooping cough. Now azithromycin is
used, which works just as well as erythromycin but doesn't affect the pylorus (and needs to be given for only five
days; you need 14 days of erythromycin for complete treatment of whooping cough).
Sulfas
The sulfas (more properly "sulfanilamides" or "sulfonamides") were the first antibiotics to be developed; they are
actually completely man-made. They interfere with certain "manufacturing" systems in the bacterial cell, including ones
that bacteria use to produce new DNA for new bacteria. Sulfas can stop bacteria from growing, but they cannot
actually kill the bacteria.
When they were first used, sulfas worked against many kinds of bacteria. Unfortunately, as with penicillin, the more
we used the sulfas the more bacteria became resistant to it. Sulfas also have a tendency to produce allergic reactions - different than those we see with the penicillins, for the most part, but including some that are rare but lifethreatening. Because of this we don't use sulfas nearly as much as we used to, and most often when we use sulfas it's
in combination with another drug which attacks a different part of the bacteria (an attack on two fronts is usually
better than an attack on one). The drugs we usually combine with sulfas are either erythromycin or "trimethoprim"
(see below); these combinations usually can kill bacteria rather than just slowing them down. One frequent use of
"plain" sulfas is in antibiotic eyedrops used for conjunctivitis ("pink eye").
Trimethoprim-Sulfamethoxazole
Trimethoprim (TMP) is another man-made antibiotic. Like the sulfas, trimethoprim blocks an important step in the
bacteria's system for making new DNA -- but it's a different step. By itself, TMP can kill bacteria, but very slowly.
Usually, though, we use TMP in combination with sulfamethoxazole (SMX), and the combination of TMP and a sulfa
kills bugs better. In fact, bacteria that are partly resistant to either TMP or SMX can still be killed by the combination of
the two. The side effects of the combination are the same as those of the two separate components.
Other Antibacterials
Nitrofurantoin
Nitrofurantoin is another synthetic antibiotic, used mainly for urinary tract infections. (Since it is excreted in the urine,
it concentrates in the bladder very nicely.) Nitrofurantoin stops bacteria from growing, and can kill bacteria with a high
enough level, by blocking the bacteria's ability to use energy it makes by "digesting" nutrients like sugar, and by
blocking other chemical reactions that use the same system. It is not usually used for infections other than UTIs, and
there are several side effects (ranging from stomach upset to (very rarely) malfunctioning nerves) which limit its use.
Aminoglycosides
The aminoglycosides are drugs which stop bacteria from making proteins; they work by attaching permanently to the
protein machinery. Since they attach permanently, the bacterial cell will die if it gets enough of the drug. They can be
used by themselves, or along with penicillins or cephalosporins to give a two-pronged attack on the bacteria.
Aminoglycosides work quite well, but bacteria can become resistant to them. The drawbacks are large, though. Since
aminoglycosides are broken down easily in the stomach, they can't be given by mouth and must be injected or given
IV (although we can use them as eyedrops for "pink eye"). When injected, their side effects include possible damage
(temporary or permanent) to the ears and to the kidneys; this can be minimized by checking the amount of the drug
in the blood and adjusting the dose so that there is enough drug to kill bacteria but not too much of it. Generally,
aminoglycosides are given for short time periods, and in the hospital where both the drug levels and the bacteria's
sensitivity can be checked easily.
Quinolones
The quinolones, of which the best known is ciprofloxacin (Cipro®:), interfere with an enzyme called DNA gyrase that is
essential for duplication of bacterial DNA. (Bacteria have only one long chromosome (DNA molecule); the chromosome
gets twisted during replication, like a telephone cord, and, again like the telephone cord, the chromosome can become
so twisted that nothing more can be done with it. DNA gyrase is the "untwisting" enzyme.) This interference is
completely different from the interference of other antibiotics with bacterial "machinery", and so bacteria that are
resistant to other antibiotics may be sensitive to the quinolones.
However, bacteria can develop resistance to the quinolones, too. Also, researchers have noticed that young animals
given quinolones can have damage to their cartilage (the hard but slippery material that connects some bones and
covers the slding surfaces of joints). In the past we have avoided using quinilones in children because of this finding,
but we sometimes have to give some children quinolones when there is no alternative antibiotic available.
Polymyxin B
Polymyxin B is an antibacterial that is produced by another bacteria. It kills bacteria by damaging the cell wall
chemically -- just the way soap does. It can't be taken internally, but it's very useful for skin infections (it's part of
"Polysporin") and for conjunctivitis ("pink eye").
Tetracyclines
Tetracyclines are yet another family of antibiotics oringinally found in bacteria. They also block the protein-making
machinery of certain bacteria. One of the tetracyclines, doxycycline, is often used to treat certain sexually transmitted
diseases (such as chlamydia and gonorrhea) in older patients. One known side effect of the tetracyclines is that they
affect development of bone and of tooth enamel in young children, and because of this we do not usually give
tetracyclines to children under age 8 years. However, tetracycline may be the best antibiotic for some life-threatening
infections, such as cholera and anthrax, and in such cases we may use tetracycline to treat a young child (tetracycline
often leaves a permanent brown stain on developing teeth, but that's better than death...).
Antifungals
Some microorganisms, known as fungi (fungus in the singular), are cells that are biologically more similar to animal
cells than to bacteria. Since many of the antibacterial antibiotics take advantage of the difference between bacterial
cells and animal cells, the fungi's similarity to animal cells makes them immune to the antibacterial antibiotics.
However, there are antibiotics available for fungi such as Candida. These include nystatin, the azoles (including
fluconazole, ketoconazole, and similar antibiotics), and amphotericin B. These work by disrupting the fungal cells'
machinery. Some of these antibiotics may be applied to the skin or taken by mouth, while others must be given IV.
Antivirals
Since viruses can't live outside the person or animal they infect, they are much harder to kill off. Our immune system
can find and kill many of the viruses that attack us, but sometimes a virus can multiply and overwhelm the immune
system before the immune system "comes up to full speed". We immunize or vaccinate people against diseases -mostly viral, but some bacterial -- so that their immune systems do have that head start. That seems to be the most
successful way to kill viruses permanently. An example is smallpox, which has been eradicated due mainly to the use
of vaccines against it -- without which the virus killed thousands, if not millions, in epidemics. Some viruses, such as
HIV (which specifically attacks the immune system), are very hard to become immune to, but a great deal of research
is being aimed at producing a working vaccine for those diseases.
Unfortunately, since viruses are
attacked biologically unless they
and all of the antiviral medicines
viruses in the environment if we
completely dormant outside a "host" (an infected human or animal), they can't be
infect someone. The immune system can't go after the virus unless it's in the body,
we have work only when the virus is trying to reproduce in the body. We can destroy
know they are there (an example is using household bleach to kill HIV that might be
on equipment contaminated with body fluids). Once the virus is in the body, however, all we can do is let the immune
system do its work, and in very rare cases (perhaps half-a-dozen viruses at most) give drugs that slow down the
infection so that the body can clear it out more easily.
Acyclovir
One often-used antiviral medicine is acyclovir; ganciclovir and valciclovir are similar to acyclovir. These medicines slow
down infections with viruses of a certain family, which include both varicella (chickenpox and shingles) and the herpes
viruses. Acyclovir slows down the virus' multiplication and therefore slows down the infection. The problem is that the
varicella and herpes viruses are never actually eradicated -- they stay in the body forever, and "reactivate" later
(sometimes years later). The recurrent sores of herpes, and the appearance of shingles years after you have
chickenpox, are examples of reactivation, and although acyclovir can help you get over the reactivation infection, it
can't actually get rid of the viruses.
AZT and other Reverse-Transcriptase Inhibitors
Another very well-known antiviral is triazidothymidine, better known as zidovudine or AZT. This drug, and others like
it, are used to inhibit an enzyme called "reverse transcriptase" which HIV uses to "copy" its own genes into the genes
of the cells it infects. Once the HIV genes are copied, the infected cell and all its offspring can produce more HIV. (This
is why an AIDS patient cannot actually get rid of all of the virus once infected: the virus may lie dormant as inactive
genes for months or years, and the anti-AIDS drugs cannot get to the gene copies.) Like bacteria, viruses can mutate,
changing their structure so that drugs that used to work no longer help; this explains why AZT and other reversetranscriptase inhibitors eventually lose their effectiveness in many patients.
Protease Inhibitors
A newer class of anti-AIDS drugs, the protease inhibitors, work by blocking a different HIV enzyme. HIV uses reverse
transcriptase to copy its genes into the cell it's infecting; it uses "protease" (an enzyme that breaks down protein) to
get into the cell in the first place. Many people with AIDS have been able to eliminate the virus from their bloodstream
-- or almost eliminate it -- by using both reverse-transcriptase inhibitors and protease inhibitors at the same time.
However, since the virus has copied itself into cells where neither kind of drug can attack it, a patient must keep taking
the drugs forever to keep the virus from reactivating.
Note, by the way, that the antiviral drugs, even more than the antibacterials, are tailored to the kind of viruses they
are intended to attack. AZT won't do anything for a cold, and neither will acyclovir. In fact, there are -- so far -- no
antivirals that will do anything for the common cold. And, since there are many different viruses in several different
families that can cause colds, we are not likely to have any anti-common-cold drugs in the near future.
The Common Cold
Since most colds are due to viruses attacking the mucus membranes of the nose and throat, the only way to get over
the cold is to wait for your immune system to get rid of the virus, and for your body to produce a new, virus-free
mucus membrane surface. Resurfacing the mucus membranes takes 3-4 days (you automatically resurface the
membranes every 3-4 days), but getting rid of the virus takes a week or two, and until the virus is gone the new
membranes will keep getting infected. Since we have no medicines that will slow down the cold viruses, we can't do
anything to speed up this process. Antibacterial antibiotics will do nothing to help get rid of the virus, and giving
antibacterial antibiotics when there is a viral cold will likely do nothing except help the bacteria in the nose and throat
become resistant -- which makes the next bacterial infection much harder to treat.
ARV’s
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such
drugs, typically three or four, are taken in combination, the approach is known as highly active antiretroviral
therapy, or HAART. The American National Institutes of Health and other organizations recommend offering
antiretroviral treatment to all patients with AIDS. Because of the complexity of selecting and following a regimen, the
severity of the side-effects and the importance of compliance to prevent viral resistance, however, such organizations
emphasize the importance of involving patients in therapy choices, and recommend analyzing the risks and the
potential benefits to patients without symptoms.
There are different classes of antiretroviral drugs that act at different stages of the HIV life-cycle.
Classes of drugs
Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits.
 Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI) inhibit reverse transcription by being
incorporated into the newly synthesized viral DNA and preventing its further elongation.
 Non-nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase directly by binding to the
enzyme and interfering with its function.
 Protease inhibitors (PIs) target viral assembly by inhibiting the activity of protease, an enzyme used by HIV to
cleave nascent proteins for final assembly of new virons.
 Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA
of the infected cell. There are several integrase inhibitors currently under clinical trial, and raltegravir became
the first to receive FDA approval in October 2007.
 Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by
blocking one of several targets. Maraviroc and enfuvirtide are the two currently available agents in this class.
 Maturation inhibitors inhibit the last step in gag processing in which the viral capsid polyprotein is cleaved,
thereby blocking the conversion of the polyprotein into the mature capsid protein (p24). Because these viral
particles have a defective core, the virions released consist mainly of non-infectious particles. There are no
drugs in this class currently available, though two are under investigation, bevirimat and Vivecon.
 AV-HALTs (AntiViral HyperActivation Limiting Therapeutics or 'virostatics') combine immunomodulating and
antiviral properties to inhibit a specific antiviral target while also limiting the hyper-elevated state of immune
system activation driving disease progression.
 Broad spectrum inhibitors. Some natural antivirals, such as extracts from certain species of mushrooms like
Shiitake and Oyster mushrooms, may contain multiple pharmacologically active compounds, which inhibit the
virus at various different stages in its life cycle. Researchers have also isolated a protease inhibitor from the
Shiitake mushroom.
Fixed-dose combinations
Fixed dose combinations are multiple antiretroviral drugs combined into a single pill.
Synergistic enhancers
Synergistic enhancers either do not possess antiretroviral properties alone or are inadequate or impractical for
monotherapy, but when they are taken concurrently with antiretroviral drugs they enhance the effect of one or more
of those drugs (often by altering the metabolism of antiretrovirals). These include ritonavir, which is an antiretroviral
drug that belongs to the class of protease inhibitors. It can, however, be administered at a "baby" dosage to reduce
the liver metabolism of other antiretroviral drugs. This principle was first exploited in the drug Kaletra (Abbott), which
is a combination of ritonavir with the protease inhibitor lopinavir at a ratio (v/v) of 1:4. Ritonavir is also used as an
enhancer of other protease inhibitors such as saquinavir and atazanavir, and of the investigational integrase inhibitor,
GS-9137. Other synergistic enhancers are being investigated for this purpose.
Combination therapy
The life cycle of HIV can be as short as about 1.5 days from viral entry into a cell, through replication, assembly, and
release of additional viruses, to infection of other cells. HIV lacks proofreading enzymes to correct errors made when it
converts its RNA into DNA via reverse transcription. Its short life-cycle and high error rate cause the virus to mutate
very rapidly, resulting in a high genetic variability of HIV. Most of the mutations either are inferior to the parent virus
(often lacking the ability to reproduce at all) or convey no advantage, but some of them have a natural selection
superiority to their parent and can enable them to slip past defences such as the human immune system and
antiretroviral drugs. The more active copies of the virus the greater the possibility that one resistant to antiretroviral
drugs will be made, so antiretroviral combination therapy defends against resistance by suppressing HIV replication as
much as possible.
Combinations of antiretrovirals create multiple obstacles to HIV replication to keep the number of offspring low and
reduce the possibility of a superior mutation. If a mutation that conveys resistance to one of the drugs being taken
arises, the other drugs continue to suppress reproduction of that mutation. With rare exceptions, no individual
antiretroviral drug has been demonstrated to suppress an HIV infection for long; these agents must be taken in
combinations in order to have a lasting effect. As a result, the standard of care is to use combinations of antiretroviral
drugs. Combinations usually comprise two nucleoside-analogue RTIs and one non-nucleoside-analogue RTI or
protease inhibitor. This three drug combination is commonly known as a triple cocktail.
Combinations of antiretrovirals are subject to positive and negative synergies, which limit the number of useful
combinations. For example, Didanosine and AZT inhibit each other, so taking them together is less effective than
taking either one separately. Other issues further limit some people's treatment options from antiretroviral drug
combinations, including their complicated dosing schedules and often severe side-effects.
In recent years, drug companies have worked together to combine these complex regimens into simpler formulas,
termed fixed-dose combinations. For instance, two pills containing two or three medications each can be taken twice
daily. This greatly increases the ease with which they can be taken, which in turn increases adherence, and thus their
effectiveness over the long-term. Lack of adherence is a primary cause of resistance development in medicationexperienced patients. Patients able to adhere at this rate and higher can maintain one regimen for up to a decade
without developing resistance. This greatly increases chances of long-term survival, as it leaves more drugs available
to the patient for longer periods of time.
Initiation of HAART
Antiretroviral drug treatment guidelines have changed many times. Early recommendations attempted a "hit hard, hit
early" approach. A more conservative approach followed, with a starting point somewhere between 350 and 500 CD4+
T cells/mm³. The current guidelines use new criteria to consider starting HAART, as described below. However, there
remain a range of views on this subject and the decision of whether to commence treatment ultimately rests with the
patient and their doctor.
The current guidelines for antiretroviral therapy (ART) from the World Health Organization reflect the 2003 changes to
the guidelines and recommend that in resource-limited settings (that is, developing nations), HIV-infected adults and
adolescents should start ART when HIV infection has been confirmed and one of the following conditions is present:
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Clinically advanced HIV disease;
WHO Stage IV HIV disease, irrespective of the CD4 cell count;
WHO Stage III disease with consideration of using CD4 cell counts less than 350/µl to assist decision making;
WHO Stage I or II HIV disease with CD4 cell counts less than 200/µl.
Concerns
There are several concerns about antiretroviral regimens. The drugs can have serious side-effects. Regimens can be
complicated, requiring patients to take several pills at various times during the day, although treatment regimens have
been greatly simplified in recent years. If patients miss doses, drug resistance can develop. Also, providing antiretroviral treatment is costly and resource-intensive, and the majority of the world's infected individuals cannot access
treatment services.
Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug
regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance.
Responses to treatment in older adults
As people age, their bodies are not able to repair and rebuild damaged cells, organs or tissues as rapidly as those of
younger people. Diseases like HIV that attack and destroy the body's defenses can exacerbate this slowing and
increase the risk of developing additional medical problems like diabetes and high blood pressure, and more physical
limitations than younger adults with HIV. In the early years of the HIV epidemic (before HAART), older adults' health
deteriorated more rapidly than that of younger individuals - regardless of CD4 count. Several studies found that older
adults had lower CD4 counts at diagnosis, faster progression to an AIDS diagnosis, more opportunistic infections, and
a shorter survival rate than younger adults, regardless of when they were first diagnosed with HIV.
Recent studies have found that a person's age does not interfere with the ability of HAART to reduce viral load, but
there may be differences between younger and older people in how well the immune system responds to treatment. A
study published in AIDS (2000) by Roberto Manfredi and Francesco Chiodo examined the effect of HAART on older
people (defined as 55 or older) compared to younger people (35 or younger). The study included 21 older people (8
women, 13 men) and 84 younger people (29 women, 55 men). The researchers found that both groups responded to
HAART, especially in reducing viral load. However, CD4 counts did not increase as much in the older people relative to
the younger ones. On average, CD4 counts increased from 212 to 289 for older adults after one year of HAART.
During the same period, CD4 counts rose from 231 to 345 for younger people.
Some people may have a very low CD4 count even though they have an undetectable viral load. This may be related
to decreased activity in the thymus (the gland where CD4 cells are made). A 2001 study in AIDS conducted by
researchers in Los Angeles included 80 HIV-positive veterans (13 were over 55 and 67 were younger). Although both
groups of veterans showed dramatic reductions in viral load once they were on treatment, the researchers found
significant differences in CD4 levels at 3, 9, 15, and 18 months. After one year on HAART, average CD4 counts
increased by 50 for the older men, compared to increases of 100 for the younger ones. This difference was not related
to baseline HIV viral load, co-infection with hepatitis C, or the race/ethnicity of participants. These studies represent an
important first step in understanding how their age may affect older adults' response to HIV treatment, but more
studies are needed to understand the long-term effects of age on HAART in older adults.
Limitations of antiretroviral drug therapy
If an HIV infection becomes resistant to standard HAART, there are limited options. One option is to take larger
combinations of antiretroviral drugs, an approach known as mega-HAART or salvage therapy. Salvage therapy often
increases the drugs' side-effects and treatment costs. Another is to take only one or two antiretroviral drugs,
specifically ones that induce HIV mutations that diminish the virulence of the infection. The most common resistance
mutation to lamivudine (3TC) in particular appears to do this. Thus, 3TC can be somewhat effective even alone and
when the virus is resistant to it.
If an HIV infection becomes sufficiently resistant to antiretroviral-drugs, treatment becomes more complicated and
prognosis may deteriorate. Treatment options continue to improve as additional new drugs enter clinical trials.
However, the limited distribution of many such drugs denies their benefits to patients in the developing world.
Drug holidays (or "structured treatment interruptions"), are intentional discontinuations of antiretroviral drug
treatment. Studies of such interruptions attempt to increase the sensitivity of HIV to antiretroviral drugs. The
interruptions attempt to change the selection pressure from the drug resistance back toward resistance to the human
immune system, thus breeding a more drug-susceptible virus. HIV spends some of its life-cycle in a state where its
DNA is entirely integrated into human DNA. Under certain conditions, drug-resistant strains of the virus can remain
dormant in this state, since CD4 T-cells also are dormant when not aroused by invading organisms. The resistant strain
can then re-emerge when antiretroviral drugs are re-introduced.
Intermittent therapy is an experimental approach designed to reduce exposure to antiretroviral drugs in an effort to
mitigate side-effects. Intermittent therapy differs from treatment interruptions in that it involves using a much shorter
cycle of switching on and off the antiviral drugs. Studies of such approaches include schedules of week-on, week-off
(also known as "wowo") and five-days-on, two-days-off (also known as "foto"), which skips treatment on weekends.
They also seek to determine what kinds of patients are best suited for this approach. However, initial data suggest that
intermittent therapy is ineffective and results in drug resistance.
It is still unclear whether suppressing or even eliminating HIV will be adequate to restore normal immune function in
the long term, since HIV can damage the ability of the thymus to produce normally diverse T-cells. Also, rapid
suppression of HIV and partial restoration of the immune system sometimes produces a dangerous hypersensitivity
reaction, immune reconstitution inflammatory syndrome. Research continues in these areas.
Adverse effects
Adverse effects of antiretroviral drugs vary by drug, by ethnicity, by individual, and by interaction with other drugs,
including alcohol. Hypersensitivity to some drugs may also occur in some individuals. The following list is not complete,
but includes several of the common adverse effects experienced by patients taking some antiretroviral drugs:
 Abdominal pain
 Alopecia
 Anemia
 Asthenia
 Diarrhea
 Dizziness (Vertigo)
 Fanconi syndrome
 Flatulence
 Headache
 Hepatitis
 Hyperbilirubinemia
 Hypercholesterolemia (Dyslipidemia, Hyperlipidemia, high cholesterol)
 Hyperpigmentation (of nails, palms, or soles)
 Ingrown nails
 Insomnia
 Jaundice
 Lipodystrophy
 Liver failure
 Malaise
 Mental confusion
 Migraines
 Mitochondrial toxicity
 Mood swings
 Myalgia
 Myalgic Encephalomyelitis (chronic fatigue syndrome)
 Myopathy
 Nausea
 Neutropenia (low number of white blood cells)
 Nightmares
 Oral ulcers
 Pancreatitis
 Paresthesia (numbness)
 Peripheral neuropathy
 Rash
 Renal failure or insufficiency
 Somnolence (drowsiness)
 Stevens-Johnson syndrome
 Change in taste perception
 Vomiting
 Xeroderma (dry skin)
 Xerostomia (dry mouth)
HIV
Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired
immunodeficiency syndrome (AIDS), a condition in humans in which the immune system begins to fail, leading to lifethreatening opportunistic infections. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-
ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected
immune cells. The four major routes of transmission are unsafe sex, contaminated needles, breast milk, and
transmission from an infected mother to her baby at birth (vertical transmission). Screening of blood products for HIV
has largely eliminated transmission through blood transfusions or infected blood products in the developed world.
HIV infection in humans is considered pandemic by the World Health Organization (WHO). Nevertheless, complacency
about HIV may play a key role in HIV risk. From its discovery in 1981 to 2006, AIDS killed more than 25 million people.
HIV infects about 0.6% of the world's population. In 2005 alone, AIDS claimed an estimated 2.4–3.3 million lives, of
which more than 570,000 were children. A third of these deaths are occurring in Sub-Saharan Africa, retarding
economic growth and increasing poverty. According to current estimates, HIV is set to infect 90 million people in
Africa, resulting in a minimum estimate of 18 million orphans. Antiretroviral treatment reduces both the mortality and
the morbidity of HIV infection, but routine access to antiretroviral medication is not available in all countries.
HIV infects primarily vital cells in the human immune system such as helper T cells (to be specific, CD4+ T cells),
macrophages, and dendritic cells. HIV infection leads to low levels of CD4 + T cells through three main mechanisms:
First, direct viral killing of infected cells; second, increased rates of apoptosis in infected cells; and third, killing of
infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline
below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to
opportunistic infections.
Most untreated people infected with HIV-1 eventually develop AIDS. These individuals mostly die from opportunistic
infections or malignancies associated with the progressive failure of the immune system. HIV progresses to AIDS at a
variable rate affected by viral, host, and environmental factors; most will progress to AIDS within 10 years of HIV
infection: some will have progressed much sooner, and some will take much longer. Treatment with anti-retrovirals
increases the life expectancy of people infected with HIV. Even after HIV has progressed to diagnosable AIDS, the
average survival time with antiretroviral therapy was estimated to be more than 5 years as of 2005. Without
antiretroviral therapy, someone who has AIDS typically dies within a year.
Classification
HIV is a member of the genus Lentivirus, part of the family of Retroviridae. Lentiviruses have many common
morphologies and biological properties. Many species are infected by lentiviruses, which are characteristically
responsible for long-duration illnesses with a long incubation period. Lentiviruses are transmitted as single-stranded,
positive-sense, enveloped RNA viruses. Upon entry of the target cell, the viral RNA genome is converted to doublestranded DNA by a virally encoded reverse transcriptase that is present in the virus particle. This viral DNA is then
integrated into the cellular DNA by a virally encoded integrase, along with host cellular co-factors, so that the genome
can be transcribed. After the virus has infected the cell, two pathways are possible: either the virus becomes latent
and the infected cell continues to function or the virus becomes active and replicates, and a large number of virus
particles that can then infect other cells are liberated.
There are two species of HIV known to exist: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and
termed both LAV and HTLV-III. It is more virulent, more infective, and is the cause of the majority of HIV infections
globally. The lower infectivity of HIV-2 compared to HIV-1 implies that fewer of those exposed to HIV-2 will be
infected per exposure. Because of its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa.
Infection with HIV-1 is associated with a progressive decrease of the CD4+ T cell count and an increase in viral load.
The stage of infection can be determined by measuring the patient's CD4 + T cell count, and the level of HIV in the
blood.
HIV infection has basically four stages: incubation period, acute infection, latency stage and AIDS. The initial
incubation period upon infection is asymptomatic and usually lasts between two and four weeks. The second stage,
acute infection, lasts an average of 28 days and can include symptoms such as fever, lymphadenopathy (swollen
lymph nodes), pharyngitis (sore throat), rash, myalgia (muscle pain), malaise, and mouth and esophageal sores.
The latency stage, which occurs third, shows few or no symptoms and can last anywhere from two weeks to twenty
years and beyond. AIDS, the fourth and final stage of HIV infection shows as symptoms of various opportunistic
infections.
The initial infection with HIV generally occurs after transfer of body fluids from an infected person to an uninfected
one. The first stage of infection, the primary, or acute infection, is a period of rapid viral replication that immediately
follows the individual's exposure to HIV leading to an abundance of virus in the peripheral blood with levels of HIV
commonly approaching several million viruses per mL.
This response is accompanied by a marked drop in the numbers of circulating CD4 + T cells. This acute viremia is
associated in virtually all patients with the activation of CD8+ T cells, which kill HIV-infected cells, and subsequently
with antibody production, or seroconversion. The CD8+ T cell response is thought to be important in controlling virus
levels, which peak and then decline, as the CD4+ T cell counts rebound to around 800 cells per µL (the normal blood
value is 1200 cells per µL ). A good CD8+ T cell response has been linked to slower disease progression and a better
prognosis, though it does not eliminate the virus.
During this period (usually 2–4 weeks post-exposure) most individuals (80 to 90%) develop an influenza or
mononucleosis-like illness called acute HIV infection, the most common symptoms of which may include fever,
lymphadenopathy, pharyngitis, rash, myalgia, malaise, mouth and esophagal sores, and may also include, but less
commonly, headache, nausea and vomiting, enlarged liver/spleen, weight loss, thrush, and neurological symptoms.
Infected individuals may experience all, some, or none of these symptoms. The duration of symptoms varies,
averaging 28 days and usually lasting at least a week.
Because of the nonspecific nature of these symptoms, they are often not recognized as signs of HIV infection. Even if
patients go to their doctors or a hospital, they will often be misdiagnosed as having one of the more common
infectious diseases with the same symptoms. As a consequence, these primary symptoms are not used to diagnose
HIV infection, as they do not develop in all cases and because many are caused by other more common diseases.
However, recognizing the syndrome can be important because the patient is much more infectious during this period.
Latency stage
A strong immune defense reduces the number of viral particles in the blood stream, marking the start of the infection's
clinical latency stage. Clinical latency can vary between two weeks and 20 years. During this early phase of infection,
HIV is active within lymphoid organs, where large amounts of virus become trapped in the follicular dendritic cells
(FDC) network.
The surrounding tissues that are rich in CD4 + T cells may also become infected, and viral particles accumulate both in
infected cells and as free virus. Individuals who are in this phase are still infectious. During this time, CD4+ CD45RO+ T
cells carry most of the proviral load.
AIDS
When CD4+ T cell numbers decline below a critical level of 200 cells per µL, cell-mediated immunity is lost, and
infections with a variety of opportunistic microbes appear. The first symptoms often include moderate and unexplained
weight loss, recurring respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis), prostatitis,
skin rashes, and oral ulcerations.
Common opportunistic infections and tumors, most of which are normally controlled by robust CD4 + T cell-mediated
immunity then start to affect the patient. Typically, resistance is lost early on to oral Candida species and to
Mycobacterium tuberculosis, which leads to an increased susceptibility to oral candidiasis (thrush) and tuberculosis.
Later, reactivation of latent herpes viruses may cause worsening recurrences of herpes simplex eruptions, shingles,
Epstein-Barr virus-induced B-cell lymphomas, or Kaposi's sarcoma.
Pneumonia caused by the fungus Pneumocystis jirovecii is common and often fatal. In the final stages of AIDS,
infection with cytomegalovirus (another herpes virus) or Mycobacterium avium complex is more prominent. Not all
patients with AIDS get all these infections or tumors, and there are other tumors and infections that are less
prominent but still significant.
The Structure of HIV
HIV stands for Human Immunodeficiency Virus. Like all viruses, HIV cannot grow or reproduce on its own. In order to
make new copies of itself it must infect the cells of a living organism.
What does HIV look like?
In this computer generated image, the large object is a human CD4+ white blood cell, and the spots on its surface and
the spiky blue objects in the foreground represent HIV particles.
Outside of a human cell, HIV exists as roughly spherical particles (sometimes called virions). The surface of each
particle is studded with lots of little spikes.
An HIV
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particle is around 100-150 billionths of a metre in diameter. That's about the same as:
0.1 microns
4 millionths of an inch
one twentieth of the length of an E. coli bacterium
one seventieth of the diameter of a human CD4+ white blood cell.
Unlike most bacteria, HIV particles are much too small to be seen through an ordinary microscope. However they can
be seen clearly with an electron microscope.
HIV particles surround themselves with a coat of fatty material known as the viral envelope (or membrane). Projecting
from this are around 72 little spikes, which are formed from the proteins gp120 and gp41. Just below the viral
envelope is a layer called the matrix, which is made from the protein p17.
The proteins gp120 and gp41 together make up the spikes that project from HIV particles, while p17 forms the matrix
and p24 forms the core.
The viral core (or capsid) is usually bullet-shaped and is made from the protein p24. Inside the core are three enzymes
required for HIV replication called reverse transcriptase, integrase and protease. Also held within the core is HIV's
genetic material, which consists of two identical strands of RNA.
What is RNA?
HIV belongs to a special class of viruses called retroviruses. Within this class, HIV is placed in the subgroup of
lentiviruses. Other lentiviruses include SIV, FIV, Visna and CAEV, which cause diseases in monkeys, cats, sheep and
goats. Almost all organisms, including most viruses, store their genetic material on long strands of DNA. Retroviruses
are the exception because their genes are composed of RNA (Ribonucleic Acid).
RNA has a very similar structure to DNA. However, small differences between the two molecules mean that HIV's
replication process is a bit more complicated than that of most other viruses.
How many genes does HIV have?
HIV has just nine genes (compared to more than 500 genes in a bacterium, and around 20,000-25,000 in a human).
Three of the HIV genes, called gag, pol and env, contain information needed to make structural proteins for new virus
particles. The other six genes, known as tat, rev, nef, vif, vpr and vpu, code for proteins that control the ability of HIV
to infect a cell, produce new copies of virus, or cause disease.
At either end of each strand of RNA is a sequence called the long terminal repeat, which helps to control HIV
replication.
HIV life cycle
Entry
HIV can only replicate (make new copies of itself) inside human cells. The process typically begins when a virus
particle bumps into a cell that carries on its surface a special protein called CD4. The spikes on the surface of the virus
particle stick to the CD4 and allow the viral envelope to fuse with the cell membrane. The contents of the HIV particle
are then released into the cell, leaving the envelope behind.
Reverse Transcription and Integration
Once inside the cell, the HIV enzyme reverse transcriptase converts the viral RNA into DNA, which is compatible with
human genetic material. This DNA is transported to the cell's nucleus, where it is spliced into the human DNA by the
HIV enzyme integrase. Once integrated, the HIV DNA is known as provirus.
Transcription and Translation
HIV provirus may lie dormant within a cell for a long time. But when the cell becomes activated, it treats HIV genes in
much the same way as human genes. First it converts them into messenger RNA (using human enzymes). Then the
messenger RNA is transported outside the nucleus, and is used as a blueprint for producing new HIV proteins and
enzymes.
Assembly, Budding and Maturation
This electron microscope photo shows newly formed HIV particles budding from a human cell.
Among the strands of messenger RNA produced by the cell are complete copies of HIV genetic material. These gather
together with newly made HIV proteins and enzymes to form new viral particles, which are then released from the cell.
The enzyme protease plays a vital role at this stage of the HIV life cycle by chopping up long strands of protein into
smaller pieces, which are used to construct mature viral cores.
The newly matured HIV particles are ready to infect another cell and begin the replication process all over again. In
this way the virus quickly spreads through the human body. And once a person is infected, they can pass HIV on to
others in their bodily fluids.
Tropism
The term viral tropism refers to which cell types HIV infects. HIV can infect a variety of immune cells such as CD4+ T
cells, macrophages, and microglial cells. HIV-1 entry to macrophages and CD4+ T cells is mediated through interaction
of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells and also with chemokine
coreceptors.
Macrophage (M-tropic) strains of HIV-1, or non-syncitia-inducing strains (NSI) use the β-chemokine receptor CCR5 for
entry and are thus able to replicate in macrophages and CD4 + T cells. This CCR5 co-receptor is used by almost all
primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical
aspects of HIV infection. They appear to be the first cells infected by HIV and perhaps the source of HIV production
when CD4+ cells become depleted in the patient. Macrophages and microglial cells are the cells infected by HIV in the
central nervous system. In tonsils and adenoids of HIV-infected patients, macrophages fuse into multinucleated giant
cells that produce huge amounts of virus.
T-tropic isolates, or syncitia-inducing (SI) strains replicate in primary CD4+ T cells as well as in macrophages and use
the α-chemokine receptor, CXCR4, for entry. Dual-tropic HIV-1 strains are thought to be transitional strains of the HIV1 virus and thus are able to use both CCR5 and CXCR4 as co-receptors for viral entry.
The α-chemokine SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by downregulating the expression of CXCR4 on the surface of these cells. HIV that use only the CCR5 receptor are termed R5;
those that only use CXCR4 are termed X4, and those that use both, X4R5. However, the use of coreceptor alone does
not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection and HIV
can also infect a subtype of myeloid dendritic cells, which probably constitute a reservoir that maintains infection when
CD4+ T cell numbers have declined to extremely low levels.
Some people are resistant to certain strains of HIV. For example people with the CCR5-Δ32 mutation are resistant to
infection with R5 virus as the mutation stops HIV from binding to this coreceptor, reducing its ability to infect target
cells.
Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the seminal fluid, which
is passed from a male to his sexual partner. The virions can then infect numerous cellular targets and disseminate into
the whole organism. However, a selection process leads to a predominant transmission of the R5 virus through this
pathway. How this selective process works is still under investigation, but one model is that spermatozoa may
selectively carry R5 HIV as they possess both CCR3 and CCR5 but not CXCR4 on their surface and that genital
epithelial cells preferentially sequester X4 virus. In patients infected with subtype B HIV-1, there is often a co-receptor
switch in late-stage disease and T-tropic variants appear that can infect a variety of T cells through CXCR4. These
variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system
collapse, and opportunistic infections that mark the advent of AIDS. Thus, during the course of infection, viral
adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS. A number of studies
with subtype B-infected individuals have determined that between 40 and 50% of AIDS patients can harbour viruses of
the SI, and presumably the X4, phenotype.
HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution. The adoption of "accessory
genes" by HIV-2 and its more promiscuous pattern of co-receptor usage (including CD4-independence) may assist the
virus in its adaptation to avoid innate restriction factors present in host cells. Adaptation to use normal cellular
machinery to enable transmission and productive infection has also aided the
establishment of HIV-2 replication in humans. A survival strategy for any infectious agent is not to kill its host but
ultimately become a commensal organism. Having achieved a low pathogenicity, over time, variants more successful at
transmission will be selected.
Replication cycle
The HIV replication cycle
Entry to the cell
HIV enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its surface to receptors on the target
cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.
Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike) and both CD4 and a
chemokine receptor (generally either CCR5 or CXCR4, but others are known to interact) on the cell surface. gp120
binds to integrin α4β7 activating LFA-1 the central integrin involved in the establishment of virological synapses, which
facilitate efficient cell-to-cell spreading of HIV-1. The gp160 spike contains binding domains for both CD4 and
chemokine receptors. The first step in fusion involves the high-affinity attachment of the CD4 binding domains of
gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change,
exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor.
This allows for a more stable two-pronged attachment, which allows the N-terminal
fusion peptide gp41 to penetrate the cell membrane. Repeat sequences in gp41, HR1 and HR2 then interact, causing
the collapse of the extra-cellular portion of gp41 into a hairpin. This loop structure brings the virus and
cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.
After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase,
ribonuclease, and protease, are injected into the cell. During the microtubule based transport to the nucleus, the viral
single strand RNA genome is transcribed into double strand DNA, which is then integrated into a host chromosome.
HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin
receptors such as DC-SIGN can also be used. DCs are one of the first cells encountered by the virus during sexual
transmission. They are currently thought to play an important role by transmitting HIV to T-cells when the virus is
captured in the mucosa by DCs. The presence of FEZ-1, which occurs naturally in neurons, is believed to prevent the
infection of cells by HIV.
Replication and transcription
Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the single-stranded
(+)RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA) molecule. The
process of reverse transcription is extremely error-prone, and the resulting mutations may cause drug resistance or
allow the virus to evade the body's immune system. The reverse transcriptase also has ribonuclease activity that
degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates
a sense DNA from the antisense cDNA. Together, the cDNA and its complement form a double-stranded viral DNA that
is then transported into the cell nucleus. The integration of the viral DNA into the host cell's genome is carried out by
another viral enzyme called integrase.
This integrated viral DNA may then lie dormant, in the latent stage of HIV infection. To actively produce the virus,
certain cellular transcription factors need to be present, the most important of which is NF-κB (NF kappa B), which is
upregulated when T-cells become activated. This means that those cells most likely to be killed by HIV are those
currently fighting infection.
During viral replication, the integrated DNA provirus is transcribed into mRNA, which is then spliced into smaller pieces.
These small pieces are exported from the nucleus into the cytoplasm, where they are translated into the regulatory
proteins Tat (which encourages new virus production) and Rev. As the newly produced Rev protein accumulates in the
nucleus, it binds to viral mRNAs and allows unspliced RNAs to leave the nucleus, where they are otherwise retained
until spliced.[90] At this stage, the structural proteins Gag and Env are produced from the full-length mRNA. The fulllength RNA is actually the virus genome; it binds to the Gag protein and is packaged into new virus particles.
HIV-1 and HIV-2 appear to package their RNA differently; HIV-1 will bind to any appropriate RNA, whereas HIV-2 will
preferentially bind to the mRNA that was used to create the Gag protein itself. This may mean that HIV-1 is better able
to mutate (HIV-1 infection progresses to AIDS faster than HIV-2 infection and is responsible for the majority of global
infections).
Assembly and release
The final step of the viral cycle, assembly of new HIV-1 virons, begins at the plasma membrane of the host cell. The
Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi complex where it is
cleaved by protease and processed into the two HIV envelope glycoproteins gp41 and gp120. These are transported to
the plasma membrane of the host cell where gp41 anchors the gp120 to the membrane of the infected cell. The Gag
(p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the
HIV genomic RNA as the forming virion begins to bud from the host cell. Maturation either occurs in the forming bud
or in the immature virion after it buds from the host cell. During maturation, HIV proteases cleave the polyproteins into
individual functional HIV proteins and enzymes. The various structural components then assemble to produce a mature
HIV virion. This cleavage step can be inhibited by protease inhibitors. The mature virus is then able to infect another
cell.
Malaria
Plasmodium falciparum ring-forms and gametocytes in human blood
Malaria is a mosquito-borne infectious disease caused by a eukaryotic protist of the genus Plasmodium. It is
widespread in tropical and subtropical regions, including parts of the Americas (22 countries), Asia, and Africa. Each
year, there are approximately 350–500 million cases of malaria, killing between one and three million people, the
majority of whom are young children in sub-Saharan Africa. Ninety percent of malaria-related deaths occur in subSaharan Africa. Malaria is commonly associated with poverty, but is also a cause of povert and a major hindrance to
economic development.
Five species of the plasmodium parasite can infect humans; the most serious forms of the disease are caused by
Plasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae causes
milder disease in humans that is not generally fatal. A fifth species, Plasmodium knowlesi, is a zoonosis that causes
malaria in macaques but can also infect humans.
Malaria is naturally transmitted by the bite of a female Anopheles mosquito. When a mosquito bites an infected
person, a small amount of blood is taken, which contains malaria parasites. These develop within the mosquito, and
about one week later, when the mosquito takes its next blood meal, the parasites are injected with the mosquito's
saliva into the person being bitten. After a period of between two weeks and several months (occasionally years) spent
in the liver, the malaria parasites start to multiply within red blood cells, causing symptoms that include fever and
headache. In severe cases, the disease worsens, leading to coma and death.
A wide variety of antimalarial drugs are available to treat malaria. In the last 5 years, treatment of P. falciparum
infections in endemic countries has been transformed by the use of combinations of drugs containing an artemisinin
derivative. Severe malaria is treated with intravenous or intramuscular quinine or, increasingly, the artemisinin
derivative artesunate. Several drugs are also available to prevent malaria in travellers to malariaendemic countries (prophylaxis). Resistance has developed to several antimalarial drugs, most notably chloroquine.
Malaria transmission can be reduced by preventing mosquito bites by distribution of inexpensive mosquito nets and
insect repellents, or by mosquito-control measures such as spraying insecticides inside houses and draining standing
water where mosquitoes lay their eggs. Although many are under development, the challenge of producing a widely
available vaccine that provides a high level of protection for a sustained period is still to be met.
Signs and symptoms
Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia (caused by hemolysis),
hemoglobinuria, retinal damage, and convulsions. The classic symptom of malaria is cyclical occurrence of sudden
coldness followed by rigor and then fever and sweating lasting four to six hours, occurring every two days in P. vivax
and P. ovale infections, while every three for P. malariae. P. falciparum can have recurrent fever every 36–48 hours or
a less pronounced and almost continuous fever. For reasons that are poorly understood, but that may be related to
high intracranial pressure, children with malaria frequently exhibit abnormal posturing, a sign indicating severe brain
damage. Malaria has been found to cause cognitive impairments, especially in children. It causes widespread anemia
during a period of rapid brain development and also direct brain damage. This neurologic damage results from
cerebral malaria to which children are more vulnerable. Cerebral malaria is associated with retinal whitening, which
may be a useful clinical sign in distinguishing malaria from other causes of fever.
Species
Appearance
Periodicity
Persistent in liver?
Plasmodium vivax
tertian
yes
Plasmodium ovale
tertian
yes
Plasmodium falciparum
tertian
no
Plasmodium malariae
quartan
no
Severe malaria is almost exclusively caused by P. falciparum infection, and usually arises 6–14 days after infection.
Consequences of severe malaria include coma and death if untreated—young children and pregnant women are
especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged
liver), hypoglycemia, and hemoglobinuria with renal failure may occur. Renal failure may cause blackwater fever,
where hemoglobin from lysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and
cause death within hours or days. In the most severe cases of the disease, fatality rates can exceed 20%, even with
intensive care and treatment. In endemic areas, treatment is often less satisfactory and the overall fatality rate for all
cases of malaria can be as high as one in ten. Over the longer term, developmental impairments have been
documented in children who have suffered episodes of severe malaria.
Chronic malaria is seen in both P. vivax and P. ovale, but not in P. falciparum. Here, the disease can relapse months or
years after exposure, due to the presence of latent parasites in the liver. Describing a case of malaria as cured by
observing the disappearance of parasites from the bloodstream can, therefore, be deceptive. The longest incubation
period reported for a P. vivax infection is 30 years. Approximately one in five of P. vivax malaria cases in temperate
areas involve overwintering by hypnozoites (i.e., relapses begin the year after the mosquito bite).
Causes
A Plasmodium sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color electron
micrograph.
Malaria parasites
Malaria parasites are members of the genus Plasmodium (phylum Apicomplexa). In humans malaria is caused by P.
falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi. P. falciparum is the most common cause of infection and is
responsible for about 80% of all malaria cases, and is also responsible for about 90% of the deaths from malaria.
Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents. There have been
documented human infections with several simian species of malaria, namely P. knowlesi, P. inui, P. cynomolgi, P.
simiovale, P. brazilianum, P. schwetzi and P. simium; however, with the exception of P. knowlesi, these are mostly of
limited public health importance.
Mosquito vectors and the Plasmodium life cycle
The parasite's primary (definitive) hosts and transmission vectors are female mosquitoes of the Anopheles genus,
while humans and other vertebrates are secondary hosts. Young mosquitoes first ingest the malaria parasite by
feeding on an infected human carrier and the infected Anopheles mosquitoes carry Plasmodium sporozoites in their
salivary glands. A mosquito becomes infected when it takes a blood meal from an infected human. Once ingested, the
parasite gametocytes taken up in the blood will further differentiate into male or female gametes and then fuse in the
mosquito gut. This produces an ookinete that penetrates the gut lining and produces an oocyst in the gut wall. When
the oocyst ruptures, it releases sporozoites that migrate through the mosquito's body to the salivary glands, where
they are then ready to infect a new human host. This type of transmission is occasionally referred to as anterior
station transfer. The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent
blood meal.
Only female mosquitoes feed on blood, thus males do not transmit the disease. The females of the Anopheles genus of
mosquito prefer to feed at night. They usually start searching for a meal at dusk, and will continue throughout the
night until taking a meal. Malaria parasites can also be transmitted by blood transfusions, although this is rare.
Pathogenesis
The life cycle of malaria parasites in the human body. A mosquito infects a person by taking a blood meal. First,
sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells (hepatocytes), where they multiply
into merozoites, rupture the liver cells, and escape back into the bloodstream. Then, the merozoites infect red blood
cells, where they develop into ring forms, then trophozoites (a feeding stage), then schizonts (a reproduction stage),
then back into merozoites. Sexual forms called gametocytes are also produced, which, if taken up by a mosquito, will
infect the insect and continue the life cycle.
Malaria in humans develops via two phases: an exoerythrocytic and an erythrocytic phase. The exoerythrocytic phase
involves infection of the hepatic system, or liver, whereas the erythrocytic phase involves infection of the erythrocytes,
or red blood cells. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the
mosquito's saliva enter the bloodstream and migrate to the liver. Within 30 minutes of being introduced into the
human host, the sporozoites infect hepatocytes, multiplying asexually and asymptomatically for a period of 6–15 days.
Once in the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture of their host
cells, escape into the blood and infect red blood cells, thus beginning the erythrocytic stage of the life cycle. The
parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.
Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their hosts to
invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise
from simultaneous waves of merozoites escaping and infecting red blood cells.
Some P. vivax and P. ovale sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead
produce hypnozoites that remain dormant for periods ranging from several months (6–12 months is typical) to as long
as three years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for
long incubation and late relapses in these two species of malaria.
The parasite is relatively protected from attack by the body's immune system because for most of its human life cycle
it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected
blood cells are destroyed in the spleen. To avoid this fate, the P. falciparum parasite displays adhesive proteins on the
surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby
sequestering the parasite from passage through the general circulation and the spleen. This "stickiness" is the main
factor giving rise to hemorrhagic complications of malaria. High endothelial venules (the smallest branches of the
circulatory system) can be blocked by the attachment of masses of these infected red blood cells. The blockage of
these vessels causes symptoms such as in placental and cerebral malaria. In cerebral malaria the sequestrated red
blood cells can breach the blood brain barrier possibly leading to coma. Although the red blood cell surface adhesive
proteins (called PfEMP1, for Plasmodium falciparum erythrocyte membrane protein 1) are exposed to the immune
system, they do not serve as good immune targets, because of their extreme diversity; there are at least 60 variations
of the protein within a single parasite and effectively limitless versions within parasite populations. The parasite
switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step ahead of the pursuing immune
system.
Some merozoites turn into male and female gametocytes. If a mosquito pierces the skin of an infected person, it
potentially picks up gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the
mosquito's gut, thereby defining the mosquito as the definitive host of the disease. New sporozoites develop and travel
to the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the mosquitoes,
and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight, particularly in
P. falciparum infection, but also in other species infection, such as P. vivax.
Diagnosis
Blood smear from a P. falciparum culture (K1 strain). Several red blood cells have ring stages inside them. Close to the
center there is a schizont and on the left a trophozoite.
Since Charles Laveran first visualised the malaria parasite in blood in 1880, the mainstay of malaria diagnosis has been
the microscopic examination of blood.
Fever and septic shock are commonly misdiagnosed as severe malaria in Africa, leading to a failure to treat other lifethreatening illnesses. In malaria-endemic areas, parasitemia does not ensure a diagnosis of severe malaria, because
parasitemia can be incidental to other concurrent disease. Recent investigations suggest that malarial retinopathy is
better (collective sensitivity of 95% and specificity of 90%) than any other clinical or laboratory feature in
distinguishing malarial from non-malarial coma.
Although blood is the sample most frequently used to make a diagnosis, both saliva and urine have been investigated
as alternative, less invasive specimens.
Symptomatic diagnosis
Areas that cannot afford even simple laboratory diagnostic tests often use only a history of subjective fever as the
indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that
when clinical predictors (rectal temperature, nail bed pallor, and splenomegaly) were used as treatment indications,
rather than using only a history of subjective fevers, a correct diagnosis increased from 21% to 41% of cases, and
unnecessary treatment for malaria was significantly decreased.
Microscopic examination of blood films
The most economic, preferred, and reliable diagnosis of malaria is microscopic examination of blood films because
each of the four major parasite species has distinguishing characteristics. Two sorts of blood film are traditionally used.
Thin films are similar to usual blood films and allow species identification because the parasite's appearance is best
preserved in this preparation. Thick films allow the microscopist to screen a larger volume of blood and are about
eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the
appearance of the parasite is much more distorted and therefore distinguishing between the different species can be
much more difficult. With the pros and cons of both thick and thin smears taken into consideration, it is imperative to
utilize both smears while attempting to make a definitive diagnosis.
From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) down to as low as
0.0000001% of red blood cells. Diagnosis of species can be difficult because the early trophozoites ("ring form") of all
four species look identical and it is never possible to diagnose species on the basis of a single ring form; species
identification is always based on several trophozoites.
One important thing to note is that P. malariae and P. knowlesi (which is the most common cause of malaria in Southeast Asia) look very similar under the microscope. However, P. knowlesi parasitemia increases very fast and causes
more severe disease than P. malariae, so it is important to identify and treat infections quickly. Therefore modern
methods such as PCR (see "Molecular methods" below) or monoclonal antibody panels that can distinguish between
the two should be used in this part of the world.
Antigen tests
For areas where microscopy is not available, or where laboratory staff are not experienced at malaria diagnosis, there
are commercial antigen detection tests that require only a drop of blood. Immunochromatographic tests (also called:
Malaria Rapid Diagnostic Tests, Antigen-Capture Assay or "Dipsticks") been developed, distributed and fieldtested.
These tests use finger-stick or venous blood, the completed test takes a total of 15–20 minutes, and the results are
read visually as the presence or absence of colored stripes on the dipstick, so they are suitable for use in the field. The
threshold of detection by these rapid diagnostic tests is in the range of 100 parasites/µl of blood (commercial kits can
range from about 0.002% to 0.1% parasitemia) compared to 5 by thick film microscopy. One disadvantage is that
dipstick tests are qualitative but not quantitative - they can determine if parasites are present in the blood, but not
how many.
The first rapid diagnostic tests were using P. falciparum glutamate dehydrogenase as antigen. PGluDH was soon
replaced by P.falciparum lactate dehydrogenase, a 33 kDa oxidoreductase [EC 1.1.1.27]. It is the last enzyme of the
glycolytic pathway, essential for ATP generation and one of the most abundant enzymes expressed by P.falciparum.
PLDH does not persist in the blood but clears about the same time as the parasites following successful treatment. The
lack of antigen persistence after treatment makes the pLDH test useful in predicting treatment failure. In this respect,
pLDH is similar to pGluDH. Depending on which monoclonal antibodies are used, this type of assay can distinguish
between all five different species of human malaria parasites, because of antigenic differences between their pLDH
isoenzymes.
Prophylactic drugs
Several drugs, most of which are also used for treatment of malaria, can be taken preventively. Generally, these drugs
are taken daily or weekly, at a lower dose than would be used for treatment of a person who had actually contracted
the disease. Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their
use is usually restricted to short-term visitors and travelers to malarial regions. This is due to the cost of purchasing
the drugs, negative side effects from long-term use, and because some effective anti-malarial drugs are difficult to
obtain outside of wealthy nations.
Quinine was used starting in the 17th century as a prophylactic against malaria. The development of more effective
alternatives such as quinacrine, chloroquine, and primaquine in the 20th century reduced the reliance on quinine.
Today, quinine is still used to treat chloroquine resistant Plasmodium falciparum, as well as severe and cerebral stages
of malaria, but is not generally used for prophylaxis.
Modern drugs used preventively include mefloquine (Lariam), doxycycline (available generically), and the combination
of atovaquone and proguanil hydrochloride (Malarone). The choice of which drug to use depends on which drugs the
parasites in the area are resistant to, as well as side-effects and other considerations. The prophylactic effect does not
begin immediately upon starting taking the drugs, so people temporarily visiting malaria-endemic areas usually begin
taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving (with the
exception of atovaquone proguanil that only needs be started 2 days prior and continued for 7 days afterwards).
The use of prophylactic drugs where malaria-bearing mosquitoes are present may encourage the development of
partial immunity.
Vaccination
Immunity (or, more accurately, tolerance) does occur naturally, but only in response to repeated infection with
multiple strains of malaria.
Vaccines for malaria are under development, with no completely effective vaccine yet available. The first promising
studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice with live,
radiation-attenuated sporozoites, providing protection to about 60% of the mice upon subsequent injection with
normal, viable sporozoites. Since the 1970s, there has been a considerable effort to develop similar vaccination
strategies within humans. It was determined that an individual can be protected from a P. falciparum infection if they
receive over 1,000 bites from infected, irradiated mosquitoes.
It has been generally accepted that it is impractical to provide at-risk individuals with this vaccination strategy, but that
has been recently challenged with work being done by Dr. Stephen Hoffman, one of the key researchers who originally
sequenced the genome of Plasmodium falciparum. His work most recently has revolved around solving the logistical
problem of isolating and preparing the parasites equivalent to 1000 irradiated mosquitoes for mass storage and
inoculation of human beings.
Instead, much work has been performed to try and understand the immunological processes that provide protection
after immunization with irradiated sporozoites. After the mouse vaccination study in 1967, it was hypothesized that the
injected sporozoites themselves were being recognized by the immune system, which was in turn creating antibodies
against the parasite. It was determined that the immune system was creating antibodies against the circumsporozoite
protein (CSP) which coated the sporozoite. Moreover, antibodies against CSP prevented the sporozoite from invading
hepatocytes. CSP was therefore chosen as the most promising protein on which to develop a vaccine against the
malaria sporozoite. It is for these historical reasons that vaccines based on CSP are the most numerous of all malaria
vaccines.