Bacterial Pathogenesis

Dr. Mejbah Uddin Ahmed

Bacterial Pathogenesis Bacterial pathogens are of two types: a) Primary pathogen: Are capable of establishing infection and causing disease in previously healthy individuals. b)Opportunistic pathogens: Are capable of establishing infection and causing disease in immunocompromised individuals.

Bacterial Pathogenesis

Virulence: Is a measure of a microbe’s ability to cause disease. Both primary and opportunistic pathogens possesses several virulence factors that facilitate pathogenesis.

Pathogenesis Virulence Factors: ●Adhesins: Pili or fimbria, teichoic acid, M protein, haemaglutinin, Curli protein, slime layer, capsule. ● several enzymes: Coagulase, hyaluronidase, collagenase, IgA protease etc. ● Toxins. ● Antigenic variation. ● Anti phagocytic activity. ● Intracellular survival.

Pathogenesis Steps of bacterial Pathogenesis: Generalized sequences of events of infection are as follows: A) Transmission ( when normal flora cause disease does not need transmission). B) Evasion of primary host defense e.g. skin, mucous membrane, stomach acid etc. C) Adherence at the site of infection.

Pathogenesis Steps of bacterial Pathogenesis: D) Colonization and growth at that side. E) Disease production by toxin or invasion and inflammation. F) Host response/Immune response. G) Progression or resolution of disease.

Steps of pathogenesis A) Transmission: 1) Human to human transmission a) Direct contact. b) No direct contact. c) Vertical. d) Blood borne. a) Direct contact: Intimate close contact; e.g. sexual: Gonorrhea. b) No direct contact: Through airborne respiratory droplets, fecal contamination of food and water, fomites etc.

Steps of pathogenesis c) Vertical transmission: From mother to fetus during intrauterine and perinatal life. •Transplacental: Treponema pallidum, Listeria monocytogens. •Within birth canal: Streptococcus agalactiae, Esch. Coli, Chlamydia, N. gonorrhoeae. •Breast milk: Staph. Aureus.

Steps of pathogenesis d) Blood borne: During blood transfusion or intravenous drug use: Syphilis. 2) Nonhuman to human: a) Soil: Spore of clostridium causes wound infection. b) Water: V. cholerae, Salmonella, L. pneumophia. c)Food: Salmonella, Clostridium botulinum. d) Animal source (zoonotic).

Pathogenesis d) Animal source (zoonotic): Bacterium

Reservoir

Disease

B. anthrcis

Domestic animals

Anthrax

Yersinia

Domestic animals, Diarrhea, sepsis Rodents

Leptospira

Rat and dog

Leptospirosis

Rickettsia

Rat and dog

Rocky mounted spotted fever

Steps of pathogenesis Adhesion : Several structures are involved in adhesion by the interactions between specific receptors on the host tissue and ligands on the bacterial surface.

Steps of pathogenesis Colonization: Successful colonization is also require to acquire essential nutrients for growth. B)Immune evasion: Once colonize, pathogenic bacteria are able to evade host immune response by avoiding or neutralizing these highly efficient clearance systems.

Pathogenesis Following structures and mechanisms are involved in immune evasion: Antiphagocytic action: ●Capsule: Capsule inhibits phagocytosis by preventing interaction between antibody and C3 bound to outer membrane of bacteria and their receptors.

Pathogenesis ●Antigenic variation: Variation occurs in surface antigen during the course of infection and helps in avoidance of specific immune response directed at those antigens e.g. N. meningitidis.

Pathogenesis ● IgA protease: Several bacteria produces protease enzyme that specifically cleaves secretory IgA and helps the bacteria to persist them on he mucosal surface and resist phagocytosis.

Pathogenesis ● Serum resistance: To survive in the bloodstream some bacteria are able to resist complement mediated lysis. Which possess “O” side chain in their LPS are more resistant.

Pathogenesis ●Intracellular phagocytosis mechanisms:

survival after by following

1)Inhibition of the fusion of phagosome with lysosome by “exported repetitive protein”: e.g. Mycobacterium.

Pathogenesis 2)Inhibition of acidification of the phagosome which reduces the activity of lysosyme e.g. legionella. 3)Escape from phagosome cytoplasm e.g. Listeria.

into

the

Pathogenesis C) Disease production by invasion and inflammation:

toxins,

enzyme,

Toxins: Are either bacterial part or bacterial production, cause damage to host tissue or may interact with immune system and cause pathological effect. Two major types of toxins: a) Endotoxin b) Exotoxin.

Pathogenesis Endotoxin: LPS or LOS, of the outer membrane components of Gram-negative bacteria. They are released after lysis of bacterial cell in vitro. Cause activation of macrophages and complement via alternative pathway. Results in release of cytokines and exert their biological effect.

Pathogenesis Biological effects of endotoxin: •Activates Macrophage: IL-1 → fever. TNF → Fever and hypotension. Nitric oxide → Hypotension.

Pathogenesis Biological effects of endotoxin: • Activates complement → C3a → Hypotension, edema. C5a → Neutrophil, chemotaxis. • Activates Hagement factor (XII) → Coagulation cascade →DIC.

Pathogenesis • Exotoxin: Exotoxins are diffusible proteins secreted by bacteria. • Vary in their molecular structures, mechanism of secretion, biological function and immunological properties.

Pathogenesis Features of Endotoxin & Exotoxin: Property

Exotoxin

Endotoxin

Source

Gram-positive& Gram-negative

Gram-negative

Chemistry

Polypeptide

LPS

Location of genePlasmid /bacteriophage Toxicity

Bacterial chromosome

High(1μg is fatal) Low(100 μg fatal)

Property

Exotoxin

Endotoxin

Clinical effect

Various

Fever, shock, DIC

Mode of action

Various

TNF, IL-1

High

Poor

Antigenicity Vaccine Heat stability

Toxoids used in vaccine Destroyed at 60ºC

No Stable at 100ºC

Pathogenesis Mechanism of action of important exotoxins: Mechanism of action

Exotoxin

ADP ribosilation

Diphtheria toxin, cholera toxin, pertussis toxin etc.

Super antigen

TSST, Staph. enterotoxin

Protease

Tetanus, Botulinum toxin, Anthrax toxin.

Lecithinase

Cl. Perfringes alpha toxin.

Pathogenesis • Several important exotoxin: • Bacillus anthracis (Anthrax toxin): Edema Factor→ An adenylate cyclase → causes ↑ed level of cyclic AMP in phagocytes → ionpermeable pores in membranes. Lethal factor: Protease → cleaves phosphokinase, required for growth of cells. Protective antigen: Binds to cell surface.

Pathogenesis • Bordetella pertussis toxin: Stimulates adenylate cyclase activity → causes ↑ed levels of CAMP →causes edema and also inhibits chemokine receptor. •

Corynebacterium toxin):

diphtheriae(Diphtheria

ADP ribosylation of elongation factor-2 leads to inhibition of protein synthesis in target cells.

Pathogenesis • Vibrio cholerae(Cholera enterotoxin):

ADP ribosylation of G proteins→stimulates adenylate cyclase→increases cAMP →causes secretion of water and electrolytes. • Staph. Aureus (Toxic shock syndrome toxin):

Acts on the vascular system causing fever, shock and inflammation.

Pathogenesis • Clostridium botulinum(Botulinum toxin):

Protease that degrade protein responsible for release of acetylcholine at neuromuscular synapses resulting in flaccid paralysis • Clostridium tetani(Tetanus toxin):

Protease that inhibits release of inhibitory neurotransmitter glycine resulting in spastic type paralysis.

Pathogenesis • Staphylococcus aureus(enterotoxin): Causes release of cytokines from lymphoid cells→stimulates enteric nervous system → activates vomiting center. • Shigella dysenteriae(Shiga toxin): Enzymatically cleaves rRNA resulting in inhibition of protein synthesis in susceptible cells.

Pathogenesis Disease production by enzymes: Several enzymes secreted by bacteria play role in the pathogenesis e.g. collgenase, hyaluronidase, coagulase, protease, leukocidin, Streptokinase, DNAase etc.

Pathogenesis Important water borne diseases: •Ingestion of drinking water: Salmonella, Shigella, Campylobacter, E. coli, Vibrio cholerae. •Ingestion of water while swimming: Leptospira interrogans. • Inhalation of water aerosol: Legionella pneumophila.