Pathogenesis of bacteria
Original and development of
Bacterial Infection
Infection：
the invasion of a host organism's bodily tissues
by disease-causing organisms, their
multiplication, and the reaction of host tissues
to these organisms and the toxins they produce.
Pathogen:
A disease causing microorganism.
Nonpathogen:
A microorganism that does not cause disease.
Opportunistic pathogen:
A microorganism does not cause disease in normal conditions,
but is capable of causing disease under contain conditions.
• A bacterial infectious disease is a multi-factorial
event which depends on:
i.
Nature (virulence factors) of bacterial species or strain.
ii. Immune status of bacteria invading hosts.
iii. Environment conditions
•
Pathogenesis of microbial infection includes:
a) general process of infection
b) mechanisms of microbes causing disease
transmissibility, adherence to host cells, invasion of host cells and
tissues, toxigenicity, and ability to evade the host's immune system
pathogenesis
How a disease develops
Pathogenicity
Disease-causing ability of
microorganisms
virulence
Degree of pathogenicity
Pathogen-- Pathogenicity
The ability of a microorganism to cause disease
Factors that determine bacterial pathogenicity:
•
Virulence: The quantitative ability of a pathogen
to cause disease that containing invasiveness and
toxigenicity.
•The amount of entry
•The portal of entry
LD50 (Lethal Dose, 50%) :
The number of pathogen required to cause lethal
disease in half of the exposed hosts.
ID50 (Infective Dose, 50%) :
The number of pathogens required to cause disease
or infection in half of the exposed hosts.
Adhesion (adherence, attachment): the process of
microbes sticking to the surfaces of host cells.
Adhesion is a key initial step during infection (then invasion).
Surface molecules on a pathogen,
called adhesins or ligands, bind
specifically to complementary
surface receptors on cells of
certain host tissues.
E. Coli bacteria on
human bladder cells
Bacteria adhering to human skin
Invasiveness: The process of microbes entering host cells
or tissues as well as spread in the body.
Toxigenicity: The ability of a microorganism to produce
toxins that contributes to the development of disease.
• intracellular bacteria:
capable of living and reproducing either inside or outside cells
Listeria monocytogenes
Salmonella
Brucella
Mycobacterium
Yersinia
Neisseria meningitidis
Cryptococcus neoformans
• extracellular bacteria:
capable of replicating outside of the host cells
Source of infections
Exogenous infection
Infections caused by infectious agents that are come from the external
environment or other hosts (patient, carrier, diseased animal or animal carrier).
“carrier”: individuals infected with infectious agents but no clinical signs or
symptoms.
Endogenous infection
Infections caused by normal flora under certain conditions (opportunistic
infection)
Transmission of bacterial infection
Bacteria can be transmitted in airborne droplets to the respiratory tract, by
ingestion of food or water or by sexual contact.
Specific bacterial species are being transmitted by different routes to
specific sites in the human body:
1.
Respiratory tract (Mycobacterium tuberculosis)
2.
gastrointestinal tract (pathogenic E. coli)
3.
Genitourinary tract (Neisseria gonorrhoeae)
4.
Closely contact
5.
Insect bite (Rickettsia)
6.
Blood transfusion
7.
Skin and other mucosa (eye)
Common Diseases contracted via
the Respiratory Tract
• Common cold
• Flu
• Tuberculosis
• Whooping cough
• Pneumonia
• Measles
• Strep Throat
• Diphtheria
Mucus Membranes
• Gastrointestinal Tract
– microbes gain entrance thru
contaminated food & water or
fingers & hands
– most microbes that enter the G.I.
Tract are destroyed by HCL &
enzymes of stomach or bile &
enzymes of small intestine
Common diseases contracted via
the GastrointestinalTract
• Salmonellosis
– Salmonella sp.
• Shigellosis
– Shigella sp.
• Cholera
– Vibrio cholorea
• Ulcers
– Helicobacter pylori
• Botulism
– Clostridium botulinum
Fecal - Oral Diseases
• These pathogens enter the G.I. Tract at one
end and exit at the other end.
• Spread by contaminated hands & fingers or
contaminated food & water
• Poor personal hygiene.
Mucus Membranes of the
Genitourinary System
Gonorrhea
Neisseria gonorrhoeae
Syphilis
Treponema pallidum
Chlamydia
Chlamydia trachomatis
HIV
Herpes Simplex II
Types of bacterial infection
According to infectious state:

Inapparent or subclinical infection: The infection with no
manifesting clinical signs and symptoms.

Latent infection or Carrier state: The infection is inactive but
remains capable of producing clinical signs and symptoms.

Apparent infection: The infection with manifesting clinical signs
and symptoms.
According to infectious sites:
Local infection: The infection is limited to a small area of the body.
Generalized or systemic infection: The infection is throughout the
body, it can present as:
Bacteremia (菌血症): Bacteria enter bloodstream without propagation in
bloodstream (bloodstream only used as a channel tool for bacteria
to spread)
-Salmonella
Toxemia (毒血症): Exotoxins enter bloodstream but no bacteria in the blood.
- corynebacterium diphtheriae, clostridium tetani
According to infectious sites:
Endotoxemia (内毒素血症): Endotoxins enter bloodstream but no
bacteria in the blood.
- Shigella
Septicemia (败血症): Bacteria enter bloodstream with propagation and
release their virelent substances (e.g., toxins).
- clostridium perfringens, Yersinia pestis
Pyemia (脓毒血症)：Pyogenic bacteria enter bloodstream with
propagation and release their virulent substances, and spread
through bloodstream into the target organs to form pyogenic foci.
- staphylococcus aureus
Normal flora &
Opportunistic infections &
Hospital acquired infections
•
All humans have bacteria (normal flora) that living on their external
surfaces (skin) and their inner surfaces (Respiratory, Gastroenteric
and Genitourinary tract mucosa). Normally due to our host defenses,
most of these bacteria are harmless.
•
The infectious diseases that initiated in hospital are referred to as
nosocomial infection (Hospital acquired infection ).
Normal flora
• Microorganisms that live
on or in human bodies,
and ordinarily do not
cause human diseases
Distribution of normal flora
Skin Flora:
Various environment of the skin results in locally dense or sparse
microbial populations. Usually Gram-positive bacteria (e.g., Staphylococci
and Micrococci ) are predominating.
Oral and Upper Respiratory Tract Flora:
Various microbial floras can be found in the oral cavity (e.g., anaerobic
bacteria) and upper respiratory tract (e.g., Neisseria, Bordetella and
Streptococci ).
Gastrointestinal Tract Flora:
In normal hosts, flora in stomach are rare as well as transient, flora
in duodenum and jejunum are sparse, and ileum contains
moderately mixed flora.
Flora in large bowel is dense (109-1011 bacteria/g of the content)
and is predominantly composed of anaerobes.
Urogenital Flora:
Flora in vaginal (e.g., anaerobes and Lactobacillus) changes with the age of
the individual, pH and hormone levels.
Distal urethra contains a sparse mixed flora (e.g., Corynebacterium).
Conjunctival Flora:
Conjunctiva (eye) has few or no microorganisms. However, Haemophilus and
Staphylococcus are frequently detected.
Physiological Role of normal flora
1.
Antagonism: a) Normal flora on skin and mucosa of hosts can form biolfilm
(as a biological barrier) that acts as colonization resistance of exogenous
pathogenic microbes; b) Normal flora may antagonize exogenous
pathogens through the production of antibiotics.
2.
Trophism: Normal flora in the intestinal tract synthesize nutrients that can
be absorbed by human (e.g., vitamin K and vitamin B).
3.
Immunoenhancement: Normal flora promotes the development of local
lymphatic tissues (e.g., Peyer’s patches in the intestines).
Conditions that opportunistic
pathogens cause human diseases
• Alteration of colonization sites
• Declination of the host immunity defense
• Dysbacteriosis
-the state in which the proportion of bacterial species
and the number of the normal flora colonizing in a
certain site of a host present large-scale alteration
Opportunistic infections
(Infections caused by normal flora)
“Opportunity”
for opportunistic infection
I. Low immunity of human body: Normal flora that usually don't cause disease
in a person with a healthy immune system. If a person with a poor immunity,
some of them can cause infection.
II. Translocation of normal flora: Members of normal flora removed from the
original inhabitancy into bloodstream or other tissues, these microbes may
become pathogenic.
III. Suppression of normal flora: When some numbers of normal flora are killed
or inhibited, it creates a partial local void that tends to be filled by exogenous
microbes or microbes from other parts of the body. Such microbes behavior as
opportunists and some of them may be pathogens.
Hospital acquired infections
(Nosocomial infections)
Hospital acquired infections specially indicate the opportunistic
infections acquired during hospital stays. Formally, they are defined as
infections arising after 48 hours of hospital admission.
Hospital acquired infections can be bacterial, viral, fungal or even parasitic.
The most common pathogens
include Staphylococci,
Pseudomonas,
Escherichia coli and Saccharomyces (fungus).
Most of microbes causing hospital acquired infections usually have a high
resistance to antibiotics.
Prevention of hospital acquired infections includes personal hygiene
(patients and hospital staff), a clean and sanitary environment in hospital, and
complete sterilization of medical materials and equipments.
Generally, infection process caused by a bacterial
pathogen involves the four steps as the following:
I. Adhesion
II. Penetration and spread
III. Survival and propagation in the host
IV. Tissue injury
Any bacterial factors involved in the four steps determine the
virulence of bacteria.
i. Bacterial virulent factors
(Implying of Nature of bacterial species or strain)
In step I: Adhesion
BACTERIAL VIRULENCE FACTORS
Environmental signals often control the expression of the virulence genes.
Common signals include: Temperrature/Iron availability/low ion/
Osmolality/Growth phase/pH/Specific ions
•The fist step of bacterial infection is the adhesion to a
specific epithelial surface of the host.
•Adhesion is a specific interaction and then a specific
combination between adhesins (virulent factors) of bacteria
and their receptors on the surface of host cells.
•Adhesins include lipoteichoic acid (for G+), some of outer
membrane proteins (for G-), ordinary pilus (for both) and so
on.
Adhesion
receptor
Bacterium
adhesin
Type 1
Epithelium
P
mannose
lipoteichoic acid
F-protein
galactose
– glycolipids
– glycoproteins
E. coli fimbriae
fibronectin
i. Bacterial virulent factors
In step II: Penetration and spread
•
After the adherence, the bacteria may entered into
host cells.
•
Invasion is commonly used to describe the entry of
bacteria into host cells, implying an active role for the
organisms and a passive role for the host cells.
•
Invasion often occurs in mucosa of intestine, urinary
tract and respiratory tract, and much less in skin.
1. reside on epithelial surface for a few of bacteria
(e.g. Vibrio cholerae)
2. penetrate the epithelial barrier and invade host cells but
remain in local tissues for a few of bacteria
(e.g. Shigella spp.).
3. pass into the bloodstream and/or from there spread into
systemic sites including internal organs for many of
bacteria
(e.g. Salmonella typhi spread into spleen and liver
through bloodstream).
Invasive pathogen reach
epithelial surface
pathogen produce
hyaluronidase
Pathogens invade
deeper tissues
Degradative enzymes
• Collagenase: to destroy collagen. There are a lot of collagens in soft tissue
including connective tissue.
• Hyaluronidase: to destroy hyaluronic acid which is a major component in
the matrix of connective tissue.
• Coagulase: to coagulate fibrinogen in tissue fluid and plasma into fibrin.
(to protect bacteria from damage by many agents)
• Streptokinase/fibrinolysin: The former activates fibrinogenase to thrombin,
which results in the degradation of fibrin. And the latter directly lyse fibrin.
• Streptodornase: it is a DNase.
• Cytolysins: 1) hemolysins (to dissolve red blood cells)
2) Leukocisins (to kill leukocytes or tissue cells )
i. Bacterial virulent factors
In step III: Survival and propagation in the host
• After bacteria enter hosts, they must have anti- phagocyte
ability for surviving. Surviving is a basis for further
propagation of bacteria.
•In human body fluids, there are phagocytes, antibody,
complement and lysozyme, which can destroy extracellular
bacteria.
•Some of bacteria can produce anti-phagocyte factors.
Propagation: is the aim of bacteria entering hosts. On the
other hand, only certain number for a bacterium can cause
disease!!!
Antiphagocytic Substances
1. Polysaccharide capsules of S. pneumoniae, Haemophilus
influenzae, Treponema pallidum ; B. anthracis and Klebsiella
pneumoniae.
2. M protein and fimbriae of Group A streptococci
3. Surface slime (polysaccharide) produced as a biofilm by
Pseudomonas aeruginosa
4. O polysaccharide associated with LPS of E. coli
Antiphagocytic Substances
5. K antigen (acidic polysaccharides) of E. coli or the analogous
Vi antigen of Salmonella typhi
6. Cell-bound or soluble Protein A produced by Staphylococcus
aureus. Protein A attaches to the Fc region of IgG and blocks the cytophilic
(cell-binding) domain of the Ab. Thus, the ability of IgG to act as an opsonic
factor is inhibited, and opsonin-mediated ingestion of the bacteria is
blocked.
Protein A inhibits phagocytosis
PHAGOCYTE
Fc receptor
immunoglobulin
Protein A
BACTERIUM
M protein inhibits phagocytosis
Complement
fibrinogen
M protein
r
peptidoglycan
r
r
i. Bacterial virulent factors
In step IV: Tissue injury
Bacteria cause tissue injury by many factors
or some special mechanisms involving:
a) Exotoxin
b) Endotoxin
c) Inducement of Immunopathological
reaction
a) Exotoxin
•Definition: Exotoxin is a toxic protein or polypeptide that is
usually secreted by living bacteria.
• Produced by many Gram+ and a few of Gram- bacteria.
• Most of exotoxins have strong and specific toxicity and frequently
cause acute infection and serious effects (e.g. death).
• Antibody against exotoxin can neutralize the toxicity.
• Exotoxins become toxoids after treatment with formaldehyde.
Toxoids lose toxic properties but retains antigenicity, which can be
used as vaccines to prevent the exotoxin-mediated disease.
According to the differences of the target cells and acting
mechanisms, exotoxins can be divided into three types:
Enterotoxin: cause food poisoning:
botulin, staphylococcal enterotoxin.
Nuerotoxin: Systematic toxic effects :
diphtheria, tetanus, and streptococcal erythrogenic toxins.
Cytotoxin: Local toxic effects :
cholera, and toxigenic E. coli enterotoxins.
Antibodies (anti-toxins) neutralize
Vaccination
This child has diphtheria resulting in a thick gray coating over back of
throat. This coating can eventually expand down through airway and, if
not treated, the child could die from suffocation
neonatal tetanus patient displays
sardonic smile, lockjaw and dyspnea
Severe case of adult tetanus. The muscles
in the back and legs are very tight.
neonatal tetanus. It is completely rigid.
Tetanus kills most of the babies who get
it when newly cut umbilical cord is
exposed to dirt.
◆ Many exotoxins are called as A-B type toxins because they consist of A
and B subunits.
A subunit provides the toxic activity.
B subunit generally mediates the toxin complex molecule to adhere and
then enter the host cell.
Cell surface
Toxic
Binding
A
B
b) Endotoxins (LPS)
Endotoxin usually released by damaged G- bacteria because it is a
structural component of the cell wall.
Endotoxin is general poisonous to all mammal cells but its toxicity is much
lower than most of exotoxins.
The toxicity of LPS from different G- bacteria is similar.
Endotoxin can not become toxoids after treatment with formaldehyde.
Antibody against endotoxin can not neutralize the toxicity.
Pathophysiologic effects of LPS
LPS (endotoxin) has many pathophysiologic effects.
One of the effects is to cause inflammation by many different
ways including:
Non-specific inflammation
cytokine release
complement activation
B cell mitogen, polyclonal B cell activator and adjuvant
Stimulation of marrow and blood vessels
Cytokine release
LPS are able to induce macrophage and neutrophilic leukocyte
to synthesize and release cytokines such as interleukin 1
(IL-1), tumor necrosis factor (TNF), interferon (IFN) and so
on.
These cytokines results in inflammation reaction
Complement activation
LPS is an activator of the complement cascade.
Certain complement by-products are the attractants for
neutrophilic leukocyte.
On the other hand, in the absence of specific antibody,
complement binding bacteria will encourage phagocytes
to kill the target bacterial cells.
B cell mitogen, polyclonal B cell activator, & adjuvant
LPS is also a B cell mitogen, polyclonal B cell activator and
adjuvant, which plays a role in the development of a suitable
chronic immune response in handling the microbes if they are
not eliminated acutely.
Stimulation of marrow and blood vessels
• LPS acts on small blood vessels to increase the expression of
adhering proteins to bind leukocytes in bloodstream.
• LPS is a powerful activator to stimulate marrow to release
leukocytes.
• LPS has an effect to dilate small blood vessels.
• LPS can also activate blood coagulation system to cause
thrombus forming in small blood vessels.
Due to those pathophysiologic effects of LPS, the
following major phenomenon can be observed clinically
or experimentally:
a) Fever (LPS is a typical pyrogen)
b) Firstly leukopenia (binding to small blood vessels) and Secondly
leukocytosis (marrow stimulation)
c) Shock (dilatation of small blood vessels)
d) DIC Disseminated intravascular coagulation (thrombus forming )
e) Death from massive organ dysfunction.
Major difference between endotoxin and exotoxin
Properties
Exotoxin
endotoxin
Origin
G+ and G-
G-
Release
Secreted from living cells or Released upon bacterial
released upon bacterial lysis lysis
Composition
protein
LPS
Heat-resistance Sensitive
resistance
Immunity
High, antitoxin, toxoid
Low, no toxoid
toxicity
High, tissue specificity
Low, no tissue
specificity
c) Inducement of Immunopathological reaction
Human immune responses to bacteria may cause tissue injury by:
1.
Over-stimulation of cytokine production and complement activation by
endotoxin can cause tissue injury.
2.
Continuously generated bacterial antigens will subsequently elicit humoral
antibodies and cell mediated immunity, which resulting in chronic
immunopathological injury.
3.
Some of bacterial antigens (e.g., M protein of Streptococcus pyogenes) can
cross-react with host tissue antigens. This bacterial antigens will cause the
development of autoimmunity.
virulence
Adherence factor
invasiveness
Virulence factors
Capsule and slime layer
Invasive enzyme
exotoxin
Virulence factors
endotoxin
ii. Number of invaded bacteria
iii. Route of bacteria invading hosts
Invaded number and invading route of bacteria
•Number of invaded bacteria: 1)The more number of invaded bacteria,
the stronger for pathogenecity; 2) diversity of different bacteria in number for
pathogenicity (e.g., 50~100 cells of Vibro cholerae but 30,000~50,000 cells of
Staphylococcus aureus can cause infectious diseases).
• Route of bacteria invading host: For most of bacteria, they have
specific invading routes (e.g. Clostridum tetani infects human through wounds
and Mycobacterium tuberculosis has multiple invading routes to cause
diseases).
Summary
1) Concepts of virulence, normal flora, hospital acquired infection,
latent infection, toxemia, septicemia, endotoxemia and pyemia.
2) The physiologic role of normal flora.
3) The conditions for generation of opportunistic infection.
4) The steps relative to bacterial infection.
5) The difference between exotoxin and endotoxin.
6) Virulence of bacteria.
7) Clinical characteristics of bacterial infections.