BLS 1st & 2ND YR 2008/09

BACTERIAL PATHOGENESIS

LECTURE 2

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Why we do not get ill?

(i) the entire invading population is killed by phagocytic cells,

such as neutrophils, or circulating bacteriocidal compounds,

such as complement

(ii) the density of bacteria traversing the integument is

collectively too low to condition the tissue to allow their

population to grow or

(iii) the mutations or phase shifts required to get across the

mucosa or survive in the blood do not occur.

It is complex and strong stochastic

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Introduction

A pathogen is a microorganism that is able to cause disease in a

plant, animal or insect.

Pathogenicity is the ability to produce disease in a host

organism.

Microbes express their pathogenicity by means of their

virulence, a term which refers to the degree of pathogenicity of the

microbe.

Determinants of virulence of a pathogen are any of its genetic

or biochemical or structural features that enable it to produce

disease in a host.

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The relationship between a host and a pathogen is dynamic, since

each modifies the activities and functions of the other.

The outcome of such a relationship depends on:

the virulence of the pathogen and

the relative degree of resistance or susceptibility of the host,

mainly due to the effectiveness of the host defense mechanisms.

Introduction

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Animals and microbes

Normal flora (beneficial or ignored): GI track, skin, upper respiratory track

Virulent bacteria (actively cause disease): pathogenic islands

Opportunistic bacteria (when host with underline problem): Pseudomonas aeruginosa: cystic fibrosis/ burn

TB, Kaposi’s sarcoma (herpesvirus): AIDS

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Mechanisms of Bacterial Pathogenicity

1. Invasiveness: the ability to invade tissues.

encompasses mechanisms for

colonization (adherence and initial multiplication),

production of extracellular substances which facilitate

invasion (invasins) and

ability to bypass or overcome host defense

mechanisms.

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2. Toxigenesis: ability to produce toxins.

Bacteria may produce two types of toxins:

i. exotoxins and

ii. endotoxins.

Mechanisms of Bacterial Pathogenicity

Exotoxins are released from bacterial cells and may act at

tissue sites removed from the site of bacterial growth.

Endotoxins are cell-associated substance. (classic sense,

endotoxin refers to the lipopolysaccharide component of the

outer membrane of Gram-negative bacteria).

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Endotoxins may be released from growing bacterial cells

and cells that are lysed as a result of effective host defense

(e.g. lysozyme) or the activities of certain antibiotics (e.g.

penicillins and cephalosporins).

Hence, bacterial toxins, both soluble and cell-associated,

may be transported by blood and lymph and cause cytotoxic

effects at tissue sites

Some bacterial toxins may also act at the site of colonization

and play a role in invasion.

Mechanisms of Bacterial Pathogenicity

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Animals and microbes

Normal flora (beneficial or ignored): GI track, skin, upper respiratory track

Virulent bacteria (actively cause disease): pathogenic islands

Opportunistic bacteria (when host with underline problem): Pseudomonas aeruginosa: cystic fibrosis/ burn

TB, Kaposi’s sarcoma (herpesvirus): AIDS

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Koch’s postulates:

1. suspected pathogen must be present

2. pathogen must be isolated and grown in pure culture

3. cultured pathogen must cause the disease

4. Same pathogen must be re-isolated from the subject

Big person in microbiology

Robert Koch,1843-1910, Germany

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Bacterial pathogenesis

Infection/entry

Virulence factors

Pathogenesis

Escape of immune surveillance

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Infection/entry

Ingestion (fecal-oral)

Inhalation (respiratory)

Trauma (e.g burn)

Arthropod bite (zoonoses:

mosquito, flea, tick,

Tsetse fly)

Sexual transmission

Iatrogenic (needle stick,

blood transfusion)

Maternal-neonatal

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Bacteria, virus, fungi

Ingestion: Salmonella, Shigella, Vibrio, Clostridium etc..

Inhalation: Mycobacterium, Mycoplasma, Chlamydia etc..

Trauma: Clostridium tetani

Arthropod bite: Rickettsia, Yersinia pestis, etc.

Sexual transmission: Neisseria gonorrboeae, HIV, chlamydia, etc

Needle stick: Staphylococcus, HIV, HBV

Maternal-neonatal: HIV, HBV, Neisseria, etc.

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Modes of infectious disease transmission

Contact transmissionDirect contact (person-to-person): syphilis, gonorrhear, herpesIndirect contact (fomites): enterovirus infection, measlesDroplet (less than 1 meter): whooping cough, strep throat

Vehicle transmissionAirborne: influenza, tuberculoses, chickenpoxWater-borne (fecal-oral infection): cholera, diarrheaFood-borne: hepatitis, food poisoning, typhoid fever

Vector transmissionBiological vectors: malaria, plaque, yellow fever Mechanical vectors: E. coli diarrhea, salmonellosis

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Extracellular versus Intracellular Parasitism

Extracellular parasites

destroyed when phagocytosed.

damaging tissues as they remain outside cells.

inducing the production of opsonizing antibodies, they

usually produce acute diseases of relatively short duration.

Intracellular parasites

can multiply within phagocytes.

frequently cause chronic disease.

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The environment in a cell

Cytosol: pH=7

Phagosome: pH=6

Phagolysosome: pH=5

Adapted from: http://bio.winona.msus.edu/bates/Bio241/images/figure-04-13b.jpg

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Barrier systems

Host cell

membrane

Taken up by

phagocyte

and resist killing

Inhibitory

molecule

Mycobacterium

Production

Of antibody

Degrade

antibody

IgA protease Streptococcus

Antimicrobial

cell-mediated

response

Activate T cells

non-specifically

and

Productively

Superantigen Staphylococcus

Antimicrobial

immune

response

Vary presenting

microbial

antigen

Switch on

production of

different

antigens

Borrelia

Genetic

recombination

Streptococcus

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Virulence factors

Factors enhancing the ability of bacteria to cause disease

Example: Pseudomonas aeruginosa

Adhesins: attachment

Alginate production: mucoid layer

Exotoxin A: inhibits host protein synthesis

Exoenzyme S: interferes with phagocytic killing

Elastolytic activity: degrades elastin

Phospholipase C: damages tissue

Pyocyanin: damages tissue by ROS

Antibiotic resistance: complicates therapy

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Pathogenic action of bacteria

Tissue destruction: flesh-eating bacteria:

Clostridium perfrigens

Obstruction: Cytic fibrosis

Toxins: bacterial components that directly

harm tissue or trigger disease symptoms

Endotoxin: lipopolysaccharides

Exotoxin: A-B toxins

Immunopathogenesis

Excess immune responses

Autoimmunity

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2. Endotoxins: heat stable

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Endotoxin: lipopolysaccharide

IL-1

TNF

Pseudomonas aeruginosa

Fever

Disseminated intravascular coagulation

Septic shock

death

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Superantigens

Polyclonal T cell activation

Aberrant cytokines,

cell death

Specific T cell activation

Anti-microbes immunity

Antigen

/MHC-1

Secreted proteins

(exotoxins) that exhibit

highly potent lymphocyte-

transforming (mitogenic)

activity directed towards T

lymphocytes.

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Known and suspected association of superantigens with

animal diseases

Autoimmune diseases

Lyme disease

Multiple sclerosis

Acute diseases

Food poisoning:

Staph infections

Streptococal

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EVASION STRATEGIES (1)

Defence Microbial strategy Mechanism Example

Wash-out Bind to cell Adhesins Neisseria

Inhibit ciliary

activity

Ciliotoxic/

Ciliostatic

molecule

Bordetella

Streptococcus

Ingestion

and

killing by

phagocyte

Disrupt

Chemotaxis

cytotoxic

Leucocidins Staphylococcus

Inhibit

phagocytosis

Capsule Streptococcus

Inhibit lysosomal

fusion

Inhibitory

molecule

Mycobacterium

Multiply Unknown Listeria

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EVASION STRATEGIES (2)

Defence Microbial strategy Mechanism Example

Restrict Fe-

Lactoferrin

Transferrin

Compete Siderophore Mycobacterium

Escherichia

Activate

complement

Interfere with

alternative pathway

Fully sialylated

surface

Neisseria

Inactivate Elastase Pseudomonas

Antigen projects

beyond surface

Activation occurs

at the wrong site

Gram-negatives

Interfere with

complement-

mediated

phagocytosis

C3b receptor

competition,

microbe and

phagocyte

Streptococcus