Transcript Pathogenesis of Bacterial Infectious Diseases

Normal Flora and Bacterial Pathogenesis
• Pin Ling (凌 斌), Ph.D.
Department of Microbiology & Immunology, NCKU
ext 5632
[email protected]
• References:
1. Murray, P. et al., Medical Microbiology (5th edition)
2. Samuel Baron, Medical Microbiology (4th edition)
Outline
Normal Flora
Bacterial Pathogenesis
(Commensal Microbes)
• Introduction
• Introduction
• Host Susceptibility
• Significance of the
• Pathogenic Mechanisms
Normal Flora
• Distribution of the
Normal Flora
• Virulence Factors
Normal Flora and Pathogenesis
Outcomes of exposure to a microorganism:
Transient colonization;
Permanent colonization;
Disease
Colonization vs. infection
Colonization: establishment of a site of reproduction
of microbes on a person without necessarily
resulting in tissue invasion or damage.
Infection: growth and multiplication of a microbe in
or on the body of the host with or without the
production of disease.
Introduction of Normal Flora
1.
A diverse microbial flora => Human body
Area: the skin and mucous membranes
Time: shortly after birth until death
Number: 1014 bacteria =>1013 host cells
2.
Normal flora may:
a. Aid the host
b. Harm the host (in sometimes)
c. Exist as commensals (no effect to the host)
3.
Viruses and parasites => NOT normal microbial flora
Most investigators consider that they are not commensals
and do not aid the host.
Significance of Normal Flora-I
1.
The effect of the normal flora on the host was not well
understood until germ-free animals became available.
Cesarean Section => Germ-free animals => Isolators
w/o detectable pathogens (viruses, bacteria & others)
2.
Two interesting observations:
a. the germ-free animals lived almost twice as long as
their conventionally maintained counterparts.
b. the major causes of death were different in the two
groups.
Germ-free Animals vs Counterparts
Germ-free Animals
Regular
Counterparts
Lifespan
Twice
One
Cause of
death
Intestinal Atonia
Infection
Anatomic &
Physiological
Changes
1. Alimentary lamina
propria underdeveloped
2. No Ab
3. Intestinal epithelial cell
renewal rate down
half
Significance of Normal Flora-II
Normal flora may aid the host in several ways:
•
Aid in digestion of food
•
Help the development of mucosa immunity
•
Protect the host from colonization with pathogenic
microbes.
106 pathogenic
microbes
GI infection
w/ normal flora
10 pathogenic
microbes
w/ reduced flora after
Streptomycin treatment
GI infection
Normal Flora competing w/ Invading
Pathogens
Adopted from Samuel Baron “Medical Microbiology”
Normal flora may act as opportunistic
pathogens
Especially in hosts rendered susceptible by:
1. Immuno-suppression (AIDS & SCID)
2. Radiation therapy & Chemotherapy
3. Perforated mucous membranes
4. Rheumatic heart disease…etc.
Sites of human body that the normal flora
microbes colonize
Respiratory tract and head
outer ear, eye, mouth, oropharynx, nasopharynx
Sterile sites: sinuses, middle ear, brain, lower
respiratory tract (trachea, bronchiole, lung)
Gastrointestinal tract
esophagus, stomach, small intestine, large intestine
Genitourinary system
anterior urethra, vagina
Sterile sites: bladder, cervix, uterus
Skin
Distribution of Normal Flora in Human Body
Adopted from Smaul Baron “Medical Microbiology”
Factors Influencing Normal Flora
1. Local Environment (pH, temperature,
redox potential, O2, H2O, and nutrient
levels…).
2. Diet
3. Age
4. Health condition (immune activity…)
5. Antibiotics,…..etc
Outline
Normal Flora
Bacterial Pathogenesis
(Commensal Microbes)
• Introduction
• Introduction
• Host Susceptibility
• Significance of the
• Pathogenic Mechanisms
Normal Flora
• Distribution of the
Normal Flora
• Virulence Factors
Introduction of Bacterial Pathogenesis
1.
Infection: growth and multiplication of a microbe in or on
the body of the host with or without the production of
disease.
2.
The capacity of a bacterium to cause disease reflects its
relative pathogenicity.
3.
Virulence is the measure of the pathogenicity of an
organism.
4.
Pathogenesis refers both to the mechanism of infection
and to the mechanism by which disease develops.
Host Susceptibility
1.
Susceptibility to bacterial infections
=> Host Defenses vs Bacterial Virulence
2.
Host Defenses:
- Barriers (skin & mucus) – first line
- Innate Immune Responses (complement, macrophages &
cytokines) – the early stage
- Adaptive Immune Responses (Ag-specific B & T cells) – the
later stage
3.
Host defenses can be comprised by destructing barriers or
defective immune response.
e.x. Cystic Fibrosis => poor ciliary function => NOT clear mucus
efficiently from the respiratory tract => Pseudomonas aeruginosa
=> serious respiratory distress.
Strict pathogens
are more virulent and can
cause diseases in a normal
person.
Opportunistic pathogens
are typically members of
normal flora and cause
diseases when they are
introduced into
unprotected sites, usually
occur in people with
underlying conditions.
Pathological Mechanisms of Bacterial
Infections
1.
Bacteria-mediated
Pathogenesis
2.
Host-mediated
Pathogenesis
3.
Bacterial virulence
factors
=> bacterial factors
causing diseases
Adopted from Samuel Baron “Medical Microbiology”
Characteristics of Pathogenic
Bacteria
1. Transmissibility
2. Adherence to host cells
3. Invasion of host cells and tissue
4. Evasion of the host immune system
5. Toxigenicity
A bacterium may cause diseases by
1. Destroying tissue (invasiveness)
2. Producing toxins (toxigenicity)
3. Stimulating overwhelming host immune responses
Bacterial Virulence Mechanisms
Bacterial virulence factors
Adhesins
Pili (fimbriae)
Nonfimbrial adhesins
Invasion of host cells
Tissue damage
Growth byproducts
Tissue-degrading enzymes
Immunopathogenesis
Toxins
Exotoxins (cytolytic enzymes
and A-B toxins); enterotoxins;
superantigens;
endotoxin and other cell wall
components
Antiphagocytic factors
Intracellular survival
Antigenic heterogeneity
Antigenic variation
Phase variation
Iron acquisition
Siderophores
Receptors for
iron-containing molecules
Resistance to antibiotics
Mechanisms of acquiring bacterial virulence genes
Entry into the human body
The most frequent portals of
entry are the sites where
mucous membranes meet
with the skin. Abnormal
areas of mucous membranes
and skin are also frequent
sites of entry.
Routes:
Ingestion, inhalation, trauma,
needles, catheters, arthropod
bite, sexual transmission
: infection
: shedding
Microbial defenses against host immunologic clearance
Encapsulation (Inhibition of phagocytosis and serum
bactericidal effect)
Antigenic mimicry
Antigenic masking
Antigenic or phase variation
Intracellular multiplication
Escape phagosome
Inhibition of phagolysosome fusion
Resistance to lysosomal enzymes
Production of anti-immunoglobulin protease
Inhibition of chemotaxis
Destruction of phagocytes
Mechanisms for escaping
phagocytic clearance and
intracellular survival
Mechanisms for escaping
phagocytic clearance and
intracellular survival
Mechanisms for escaping
phagocytic clearance and
intracellular survival
Endotoxin-mediated toxicity
Fever,
leukopenia followed by leukocytosis,
activation of complement, thrombocytopenia,
disseminated intravasacular coagulation,
decreased peripheral circulation and perfusion to
major organs (multiple organ system failure),
Shock and death.
Peptidoglycan, teichoic and lipoteichoic acids of grampositive bacteria stimulate pyrogenic acute phase
responses and produce endotoxin-like toxicity
Back
Lipid A of
lipopolysaccharide
is responsible for
endotoxin activity
Pathogenesis
of sepsis
(septicemia)
Adopted from Samuel Baron “Medical Microbiology”
Regulation of bacterial virulence factors
Environmental factors often control the expression
of the virulence genes.
Common factors: temperature, iron availability,
osmolarity, growth phase, pH, specific ions, specific
nutrient factors, bacterial cell-density, interaction
with host cells.
The severity of a disease is determined
by the inoculum size of the pathogen and
the host conditions, such as congenital
defect, immunodeficiency states and
other disease-related conditions.
The symptoms of a disease are
determined by the function of the tissue
affected.
Transmission of infection
By producing asymptomatic infection or mild disease, rather than
death of the host, microorganisms that normally live in people
enhance the possibility of transmission from one person to another.
Carrier: a person or animal
with asymptomatic infection
that can be transmitted to
another person or animal.
The clinical symptoms of
diseases produced by
microbes often promote
transmission of the agents.
Zoonosis: infectious diseases
transmitted between animals
and men.
Hospital- (nosocomial) vs.
community-acquired infections
Many bacteria are transmitted on hands
Adhesion
Back
Adherence of bacterium to epithelial or endothelial
cells allow them to colonize the tissue.
Common adhesins: pili (fimbriae), slime, lipoteichoic
acid, surface proteins or lectins.
Biofilm, formed on a surface by the bacteria that are
bound together within a sticky web of polysaccharide,
is a special bacterial adaptation that facilitates
colonization on the surgical appliances (e.g., artificial
valves or indwelling catheters) and dental plaque. It can
protect the bacteria from host defenses and antibiotics.
The bacteria may invade via the M cells
Back
The A-B toxins
A chain has the inhibitory activity against some vital function
B chain binds to a receptor and promotes entry of the A chain
Back
Mode of action
Inhibition of
protein synthesis
Hypersecretion
Inhibition of
neurotransmitter
release
In many cases
the toxin gene is
encoded on a
plasmid or a
lysogenic phage
SUMMARY
1. Normal flora may aid the host in several ways:
•
Aid in digestion of food
•
Help the development of mucosa immunity
•
Protect the host from colonization with pathogenic microbes
2. Normal flora may act as opportunistic pathogens.
3. Susceptibility to bacterial infections depends on the balance between
host defenses and bacterial virulence.
4. Pathogenic mechanisms of bacterial infections include
•
Bacteria-mediated Pathogenesis
•
Host-mediated Pathogenesis
Back
Clonality of bacterial pathogens
Transfer of mobile genetic
elements within or between
species can result in
transfer of virulence factors
(e.g., pathogenicity islands).
Recombination may occur
between extrachromosomal
DNA and the chromosome
to generate new bacterial
clone.
Different clonal types of a
certain species may cause
different diseases.
Various virotypes
of E. coli