Bacterial Pathogenesis Pin Ling ( 凌 斌 ), Ph.D. Department of Microbiology & Immunology, NCKU...

Bacterial Pathogenesis

• Pin Ling ( 凌 斌 ), Ph.D. Department of Microbiology & Immunology, NCKUext 5632lingpin@mail.ncku.edu.tw

• References: 1. Chapter 19 in Medical Microbiology (Murray, P. R. et al; 5th edition) 2. 醫用微生物學 ( 王聖予 等編譯 , 4th edition)

Outline

Bacterial Pathogenesis

• Introduction

• Host Susceptibility

• Pathogenic Mechanisms

• Virulence Factors

Introduction of Bacterial Pathogenesis

1. Infection: growth and multiplication of a microbe in or on the body 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 a microorganism.

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.

Entry into the human body

: infection : shedding

The most frequent portals of entry- Mucus - Skin

Routes:

Ingestion, inhalation, traum

a, needles, catheters, arthr

opod bite, sexual transmiss

ion

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

Characteristics of Pathogenic Bacteria

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”

Bacterial Virulence Mechanisms

Bacterial virulence factors

Adhesins Pili (fimbriae) Nonfimbrial adhesins

Invasion of host cells Tissue damage

Growth byproducts Tissue-degrading enzymes

ImmunopathogenesisToxins

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

Adhesion

Adherence of bacterium to epithelial or endothelial cell

s allow them to colonize the tissue.

Common adhesins: pili (fimbriae), slime, lipoteichoic ac

id, surface proteins or lectins.

Biofilm, formed on a surface by the bacteria that are bo

und together within a sticky web of polysaccharide, is a

special bacterial adaptation that facilitates colonization

on the surgical appliances (e.g., artificial valves or indw

elling catheters) and dental plaque. It can protect the b

acteria from host defenses and antibiotics.

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The bacteria may invade via the M cells

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M (Microfold) cells

Lipid A of lipopolysaccharide is responsible for endotoxin activity

Pathogenesis of sepsis (septicemia)

Endotoxin (LPS)-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 gram-positive bacteria stimulate pyrogenic acute phase responses and produce endotoxin-like toxicity

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Endotoxin-mediated toxicity

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Superantigen-mediated toxicity

1. Bind to TCR and activate T cells w/o Ag

2. Autoimmune-like responses

3. S. aureus =>Toxic shock syndrome toxin

S. pyogenes=> Erythrogenic toxin A orC

The A-B toxins

Mode of action

Inhibition of protein synthesis

Hypersecretion

Inhibition of neurotransmitter release

A chain has the inhibitory activity against some vital function

B chain binds to a receptor and promotes entry of the A chain

In many cases the toxin gene is encoded on a plasmid or a lysogenic phage

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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

Microbial defenses against host immunologic clearance

Mechanisms for escaping phagocytic clearance and intracellular survival

Mechanisms for escaping phagocytic clearance and intracellular survival

Mechanisms for escaping phagocytic clearance and intracellular survival

Environmental factors often control the expression of t

he virulence genes.

Common factors: temperature, iron availability, osmolar

ity, growth phase, pH, specific ions, specific nutrient fa

ctors, bacterial cell-density, interaction with host cells.

Regulation of bacterial virulence factors

SUMMARY

1. 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

2. Susceptibility to bacterial infections depends on the balance between host defenses and bacterial virulence.

3. Pathogenic mechanisms of bacterial infections include • Bacteria-mediated Pathogenesis

• Host-mediated Pathogenesis

Mechanisms of acquiring bacterial

virulence genes