mechanisms of bacterial pathogenesis pin ling ( 凌斌 ), ph.d. department of microbiology &...

Mechanisms of Bacterial Pathogenesis

• Pin Ling ( 凌斌 ), Ph.D. Department of Microbiology & Immunology, NCKUext [email protected]

• 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)

Normal Flora (Commensal

Microbes) • Introduction• Significance of

the Normal Flora• Distribution of

the Normal Flora

Bacterial

Pathogenesis

• Introduction

• Host Susceptibility

• Pathogenic

Mechanisms

• Virulence Factors

Outline

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.

Outcomes of exposure to a microorganism:1. Transient colonization2. Permanent colonization 3. Disease

Normal Flora and Pathogenesis

Introduction of Normal Flora

1. A diverse microbial flora => Human body Area: the skin and mucous membranes Time: shortly after birth until deathNumber: 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 normal flora influences the anatomy, physiology,

susceptibility to pathogens, and morbidity of the host.

2. 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)

3. 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 Regular Counterparts

Lifespan Twice One

Cause of death

Intestinal Atonia Infection

Anatomic & Physiological Changes

1. Alimentary lamina propria under-developed

2. No Ab

3. Intestinal epithelial cell renewal rate down half

Germ-free Animals vs Counterparts

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

GI infectionw/ reduced flora afterStreptomycin treatment

10 pathogenic microbes

Normal Flora competing with 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 & Chemotherapy3. Perforated mucous membranes4. Rheumatic heart disease…etc.

Respiratory tract and head outer ear, eye, mouth, oropharynx, nasopharynx Sterile sites: sinuses, middle ear, brain, lower respirator

y tract (trachea, bronchiole, lung)

Gastrointestinal tract esophagus, stomach, small intestine, large intestine

Genitourinary system anterior urethra, vagina Sterile sites: bladder, cervix, uterus

Skin

Sites of human body that the normal flora microbes colonize


Distribution of Normal Flora in Human Body

1. Local Environment (pH, temperature, redox potential, O2, H2O, and nutrient levels…).

2. Diet

3. Age

4. Health condition (immune activity…)

5. Antibiotics,…..etc

Factors Influencing Normal Flora

Normal Flora (Commensal

Microbes) • Introduction• Significance of

the Normal Flora• Distribution of

the Normal Flora

Bacterial

Pathogenesis

• Introduction

• Host Susceptibility

• Pathogenic

Mechanisms

• Virulence Factors

Outline

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 (1) the mechanism of infection and to (2) the mechanism by which disease develops.

Host Susceptibility

1. Susceptibility to bacterial infections => Host Defenses vs Bacterial Virulence

2. Host Defenses: - Barriers (skin & mucus) – the first line - Innate Immunity (complement, macrophages & cytokines) – the early stage - Adaptive Immunity (Ag-specific B & Tcells)–the later stage

3. Host defenses can be comprised by destructing barriers or defective immune response. e.g. 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.

Transmission of infection

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

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.

Many bacteria are transmitted on hands

Entry into the human body

: infection : shedding

The most frequent portals of entry- Mucus - Skin

Routes:Ingestion, Inhalation, Trauma, Needlestick, Catheters, Arthropod bite, Sexual transmission

1. Transmissibility2. Adherence to host cells3. Invasion of host cells and tissue4. 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


Mechanisms of acquiring bacterial

virulence genes

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

1. Adherence of bacterium to epithelial or endothelial c

ells allow them to colonize the tissue.

2. Common adhesins: pili (fimbriae), slime, lipoteichoic

acid, surface proteins or lectins.

3. Biofilm, formed on a surface by the bacteria that are

bound together within a sticky web of polysaccharide, i

s a special bacterial adaptation that facilitates colonizat

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

ndwelling catheters) and dental plaque. It can protect t

he bacteria from host defenses and antibiotics.

Back

Bacteria may invade via the M cells

Back

M (Microfold) cells

Lipid A of lipopolysaccharide is responsible for endotoxin activity

Pathogenesis of sepsis (septicemia)

Endotoxin (LPS)-mediated toxicity

1. Fever, 2. Leukopenia followed by leukocytosis,3. Activation of complement, thrombocytopenia, 4. Disseminated intravasacular coagulation, 5. Decreased peripheral circulation and perfusion to

major organs (multiple organ system failure), 6. Shock and death.

Peptidoglycan, teichoic and lipoteichoic acids of gram-positive bacteria stimulate pyrogenic acute phase responses and produce endotoxin-like toxicity

Back

Endotoxin-mediated toxicity

Back

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 or C

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

Back

Back

The A-B toxins-II

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

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.

Regulation of bacterial virulence factors

SUMMARY-I1. 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

SUMMARY-II4. 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.

Figure 19-3 The mode of action of dimeric A-B exotoxins. The bacterial A-B toxins often consist of a two-chain molecule. The B chain promotes entry of the bacteria into cells, and the A chain has inhibitory activity against some vital function. ACH, Acetylcholine; cAMP, cyclic adenosine monophosphate. (Redrawn From Mims C et al:

Medical microbiology, London, 1993, Mosby-Wolfe.)

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mechanisms of bacterial pathogenesis pin ling ( 凌 斌 ), ph.d. department of microbiology &...

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mechanisms of bacterial pathogenesis pin ling ( 凌斌 ), ph.d. department of microbiology &...