BIO-241 – Microbiology
Host-Pathogen Interactions
Bacterial Pathogenesis
Aims and Objectives
To describe the complex interaction between bacteria and the human host, including the modes
of transmission, progression and outcome of infection. After reading this document, you should:
1. Be able to define the terms infection, pathogen, commensal, symbiosis, parasitism,
saprophytism, opportunistic infection and nosocomial infection.
2. Be familiar with Koch's postulates and their relevance to bacterial pathogenesis.
3. Be familiar with the transmission cycle, stages of progression and possible outcomes of
bacterial infection.
4. Be familiar with the spectrum of virulence mechanisms employed by micro-organisms.
In examining the mechanisms that bacteria use to cause infections, it is worth pointing out one
fact right at the start - it is the fundamental object of both humans and bacteria to survive and
prosper! Whilst some bacteria seem to do very well by causing a succession of infections,
passing from one susceptible human host to another, the majority of bacteria that we come into
contact with exist in a state of equilibrium, either living on us or in us quite peacefully. For this
second group, it is only when this happy balance is disturbed for some reason that infection may
result. Clearly there are two very important elements that control the interaction between bacteria
and humans - the defences, or immunity, employed by the human host and the virulence factors
exhibited by the bacteria that enable them to produce infection. We will be concentrating on just
one side of the picture in this section, namely the properties of the bacteria, but before doing that
we should define a few relevant terms.
Infection: This is when an organism enters the body, increases in number and causes damage to
the host in the process.
A pathogen: This is an organism that is able to evade the various normal defences of the human
host to cause infection.
Commensalism: Literally `eating at the same table'! This refers to a neutral situation where the
host and bacteria live together, but have no effect on each other's life cycle - either positive or
negative. Some authors broaden the definition to allow benefit to occur to one group through the
association, providing no damage is caused to the other. Overall, this is just about the best way to
describe the relationship that humans have with most of the normal bacterial flora of the skin and
mucus membranes, including the upper respiratory tract, the lower gastrointestinal tract and the
vagina. These bacteria are often described as non-pathogenic or commensal.
Symbiosis: This describes a situation where species live together for their mutual benefit, with
each receiving a valuable contribution from the other. There is an element of symbiosis in the
relationship between the human host and the gut flora; humans provide the bacteria with a warm,
moist, protected environment and, in return, the gut flora uses up all the available nutrients and
so makes it difficult for more pathogenic species to become established and initiate infection.
Parasitism: This describes an unequal relationship where one organism clearly benefits from an
association to the detriment of another. To some extent this happens in all infections, but the
word is often reserved for situations where the invading pathogen has quite clearly hijacked host
processes for its own benefit, such as in viral infections.
Saprophytism: This refers to the situation where one organism lives on the dead tissues of
another. Fungi often display this ability.
Opportunistic infection: This occurs when the normal human defences are so weakened that it
allows infection to take place by organisms that would not generally be able to cause infection in
a healthy human. Examples of these include the many infections that are seen in AIDS patients,
including Pneumocystis carinii pneumonia, Toxoplasma gondii brain abscesses and systemic
infections with Candida sp. and atypical Mycobacterium sp.
Nosocomial infection: These are infections that are transmitted in hospitals. Some of these may
be opportunistic infections mentioned above affecting seriously ill patients, others, for example
infections with Methicillin-Resistant Staphylococcus aureus (MRSA), may occur because of the
special nature of the hospital environment.
Stages of Infection
The time between the exposure to an agent and the first appearance of clinical symptoms is
called the incubation period and, although there are no symptoms, the organism may be causing
substantial damage during this interval. There may follow a period known as the prodrome,
where non-specific signs and symptoms such as headache, fever and lethargy are noted, before
the development of a specific symptom complex suggestive of a classical infectious disease such
as pneumonia, meningitis or diarrhoea. Once the acute stage has passed, a period of resolution
occurs, where the severity of the symptoms gradually decreases, and finally convalescence where
the symptoms have largely gone, but the body is still recovering.
The time course and severity of the disease depends upon the balance between the virulence of
the infecting agent and the success with which the immune system combats the organism. Some
infections may occur which are not sufficiently severe to produce clinical symptoms and these
are called asymptomatic or subclinical infections. Clinical infection has a number of outcomes
covering the spectrum between death and complete recovery. The term chronic infection is selfexplanatory, but carriage is a term that has been used rather loosely. In bacteriology, it is often
used to describe the situation where a person continues to harbour a pathogenic organism but
suffer no ill-effects themselves, examples being Salmonella typhi in the gut and
Corynebacterium diphtheriae in the respiratory tract, but in virology the persistent virus may be
associated with low level damage, an example being hepatitis B infection. Latency refers to a
situation where an agent persists in a dormant, inactive form without causing damage, but which
may reactivate to cause problems at a later date; an example is herpes simplex virus which lies
dormant within dorsal root ganglia after the primary infection, but may periodically reactivate to
cause cold sores.
Studies of Bacterial Pathogenesis
Some of the earliest and most influential work in this area was performed by the German
microbiologist, Robert Koch, in the late nineteenth century. In identifying the bacteria
responsible for diseases such as anthrax and tuberculosis, he described a number of requirements
that must be satisfied before an organism can definitely be regarded as the cause of the disease.
These conditions have become known as Koch's postulates and they can be summarized as
follows:
1. The organism occurs in every case of the disease and under circumstances which account
for the pathological changes and clinical course of the disease.
2. The organism occurs in no other disease as a fortuitous and non-pathogenic finding.
3. After being isolated from the body and grown in pure culture, the organism will
repeatedly produce exactly the same clinical disease when inoculated into a new host.
These ideas have formed the foundation for all our ideas about infectious diseases, although it is
now becoming increasingly clear that they can no longer be applied in all situations. For
example, they do not take account of advances in serological diagnosis nor the recent
developments in molecular biology looking at agents that cannot be cultured in the laboratory.
They also seem less appropriate when considering infections by commensal organisms in
immunosuppressed patients, a group that has become much more important as a result of the
advances in modern medical care. Our current medical ethics would prevent many of the human
challenge studies that were carried out in the past and for many infections there is no acceptable
animal model of infection. However, we should not forget that Koch's postulates have been an
extremely valuable tool over the years because they have provided a firm scientific basis to
studies of bacterial pathogenesis. This work has revealed a number of steps in the development
of infection which are still very relevant to all of today's infections.
Contact with the Host
Transmission
Clearly the commensal flora is already in intimate contact with the host, but these organisms are
of low pathogenicity and are usually held in check by the immune mechanisms described below.
More pathogenic organisms, that are not normal parts of the commensal flora, have developed
numerous strategies that allow them to move from a source or reservoir to the susceptible host in
a viable state. The spores that are produced by some bacteria and fungi, and bacteria such as
Mycobacterium tuberculosis, are very resistant to the effect of drying in the environment. Gram
positive organisms such as Staphylococcus aureus seem to be very well adapted to surviving on
skin surfaces such as the hands and this is a very important route of transmission within
hospitals. Gram negative organisms can be adept at surviving in fluids; contaminated water
supplies are usually responsible for infection with Vibrio cholerae whilst major outbreaks of
infection have occurred in hospitals due to contamination of fluids used in medicine by bacteria
such as Klebsiella. Other bacteria, such as Salmonella and Shigella, thrive under conditions of
poor hygiene and are transmitted by faecal-oral spread, whilst more fragile organisms, such as
Neisseria gonorrhoeae, may require the most intimate contact of all.
Protection of External Surfaces
The skin normally represents an impenetrable barrier to micro-organisms and mucosal surfaces,
such as those of the respiratory tract and the gut, are protected by a number of factors including
the secretion of mucus, powerful proteolytic enzymes, antibodies (particularly IgA) and the high
turnover of surface cells.
Injections, vascular lines, accidental trauma, surgery and conditions such as eczema, all
breakdowns the integrity of the skin and increase the chance of infection. Increased risks of
infections are also seen when the mucosal defences are disturbed: this includes alterations in
mucus distribution in long term smokers; production of specific IgA proteases by bacteria such
as Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae; and the loss
of mucosal endothelial integrity as a side effect of modern cytotoxic therapy.
Adherence
Many of the body surfaces are washed by fluids, including mucus in the upper respiratory tract
and the gut, peristalsis of gut contents throughout the bowel and the movement of urine in the
urinary tract. If a bacterium is to multiply and cause infection it must have some way of fixing its
position and becoming established.
This adherence is produced by bacterial adhesins or ligands that bind specifically to host
molecules known as receptors. These adhesins can be proteins found on the bacterial cell wall /
membrane or they can be collected together on structures that project from the cell surface, for
example fimbriae and pili, which seem to be expressly aimed at increasing the chance of
adherence. A huge number of bacterial adhesins and their associated host cell receptors have
been described, but one of the most well-studied concerns the ability of certain strains of
Escherichia coli to cause urinary tract infection. Studies of E. coli isolates have shown that only a
relatively small number of types are found in urinary tract infections, although there are many
more types to be found nearby colonising the human gut. The reason seems to be that strains that
express the type 1 pilus can attach to the Tamm-Horsfall protein in the mucus of the lower
urinary tract and this prevents them being flushed away by the flow of urine; if they do manage
to ascend the urethra into the bladder, strains of E. coli that do not express this pilus cannot
adhere and are immediately washed out. However, when the isolates from upper urinary tract
infections are examined, a different pattern is seen. It appears that these E. coli strains that have
swam up against the flow of urine in the ureters may change their cell surface such that they now
express P pili that allows them to attach to the P blood group antigen that is found on the cells in
the renal pelvis.
Bacteria may also secrete viscous substances onto their surface which increase adherence in a
non-specific fashion. This would include alginate capsule production by Pseudomonas
aeruginosa in the lungs of cystic fibrosis patients and the production of polysaccharide slime by
Staphylococcus epidermidis when it colonizes intravenous lines.
Entry into Cells and Tissues
Certain agents take the attachment process a stage further by using adhesins as the first step
towards promoting their uptake into the host cell. The entry of Listeria monocytogenes into
phagocytic cells following its attachment to the complement receptor CR3 is one example of this
amongst bacteria, but all viruses need to use this mechanism to produce infection. Human
immunodeficiency virus (HIV) uses a protein on its surface called gp120 to target CD4-bearing
T lymphocytes and initiate uptake, whilst influenza virus attaches and enters cells using a protein
called haemagglutinin as the adhesin and neuraminic acid on the surface of respiratory
epithelium as the receptor.
Entry into cells may lead to an infection that is limited to that cell type, or it may be a first step
towards wider dissemination of the infecting agent throughout the body. As an alternative to
bypassing the epithelium through intracellular invasion, some bacteria penetrate this barrier by
squeezing through the junctions between adjacent epithelial cells and so reach deeper tissues.
Production of Disease
Once a bacterium has entered the body, there are a number of ways in which it can cause disease.
It may produce damage to local tissues as well as damage to distant tissues through the action of
bacterial toxins, although this distinction may not be clear cut as there is nothing to stop toxins
from acting locally too. Bacteria must continue to evade the responses of the immune system
and, although it will not be discussed here, it is important to remember that an excessive immune
response may itself produce a great deal of damage and be responsible for many of the symptoms
of disease.
Local Effects
Certain bacteria cause diffuse infections by producing enzymes that enable them to breakdown
the cells and intracellular matrices of host tissues. Streptococcus produce the enzyme
hyaluronidase which hydrolyses hyaluronic acid, a polysaccharide component responsible for
binding cells together. Clostridium produce a similar enzyme called collagenase and many
bacteria produce different kinases, lecithinases and proteases with varying effects upon host
tissues. On the other hand, some bacteria produce more localised infections with the production
of pus in the affected tissues; bacteria that do this are described as pyogenic. Staphylococcus
aureus produces an enzyme coagulase which coagulates fribrinogen and abscesses are
particularly likely to develop where infections involving Bacteroides fragilis take place.
Distant Effects
There are over 220 known bacterial toxins and they can be divided up into two groups.
Endotoxin is a component of the cell wall of all gram negative bacteria whilst the exotoxins
include a huge number of proteins that are secreted from the bacterial cell and which are mostly,
but not exclusively, produced by gram positive bacteria.
Endotoxin is the lipid portion of lipopolysaccharide, lipid A, and is a potent inducer of
interleukin-1 (IL-1) from macrophages, which resets the hypothalamus to produce fever, and
tumour necrosis factor (TNF) from phagocytes, which induces severe shock. The toxin is
effective when it is present within the cell walls of living bacteria, but its greatest effect is
usually seen when bacteria are killed, lysed and their products released into the systemic
circulation.
Exotoxins are often divided up into three main groups, although not every toxin falls neatly into
these categories. Cytotoxins destroy host cells and an example of this is the alpha-toxin of
Clostridium perfringens. Neurotoxins interfere with neural transmission, famous examples being
the toxins of Clostridium tetani and Clostridium botulinum. Enterotoxins affect the cells lining
the gastrointestinal tract, and the enterotoxins of Staphylococcus aureus and many of the toxins
produced by Escherichia coli are examples of this.
Evasion of Host Defenses
The host tissue is a hostile environment for bacteria and they need to develop strategies for
maintaining their nutrition. The acquisition of iron is particularly important, as its availability is
tightly controlled by the host. Most pathogenic organisms have developed a number of secretory
proteins, called siderophores, which can steal iron from host carrier-proteins and so make it
available to bacteria.
Some bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella
pneumoniae, and the fungus Cryptococcus neoformans produce a glycocalyx capsule that
inhibits phagocytosis. Mycobacterium tuberculosis accomplishes this by the insertion of waxes
into its cell wall and Streptococcus pyogenes has the M protein in its cell wall to decrease
phagocytosis. Staphylococcus and Streptococcus use leukocidins to destroy leukocytes and
macrophages and haemolysins to disrupt erythrocytes. The parasite Trypanosoma undergoes
rapid antigenic variation to evade the host's immune response and some viruses, such as human
immunodeficiency virus, actually infect the cells of the immune system themselves.
Choosing a New Victim!
The final stage in the infection cycle is for the agent to find a new host to infect which usually
ties in with how the present host first acquired the disease. Thus bacteria that cause sexually
transmitted diseases, such as Chlamydia trachomatis and Neisseria gonorrhoeae, will tend to
multiply and produce a discharge from the urethra or endocervix and so maximise their chances
of being passed on to the next sexual contact. Bacteria that are spread by the faecal-oral route,
such as Salmonella and Shigella, tend to multiply within the gut and produce diarrhoea, which
challenges an individual's hygiene and increases their chance of transmission. The many agents
that use the respiratory route for infection tend to produce symptoms such as nasal discharge,
coughing and sneezing which enhances the production of aerosols and therefore the potential for
transfer to new hosts.