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6/10/2011 Mechanisms of Pathogenicity The Microbes Fight Back Medically important bacteria Bacillus anthracis Campylobacter Clostridium botulinum Clostridium difficile Clostridium tetani Corynebacterium diphtheriae Enterococcus Escherichia coli ETEC O157:H7 Mycobacterium tuberculosis Neisseria gonorrhoeae Pseudomonas aeruginosa Salmonella Shigella dysenteriae Shigella sonnei Staphylococcus aureus Staph. epidermidis Streptococcus pyogenes (Group A) Strep. pneumoniae Treponema pallidum Vibrio cholerae Yersinia enterocolitica Yersinia pestis Eukaryotic parasites Giardia species Schistosoma species Plasmodium species Viruses Herpes viruses Influenza virus Smallpox virus Human immunodeficiency virus ***this is not intended to be a complete list**** Mechanisms of Pathogenesis •Production of toxins that are then ingested •Colonization of surface of the host, followed by toxin production •Invasion of host tissues •Invasion of host tissues followed by toxin production 1 6/10/2011 Mechanisms of Pathogenesis •Production of toxins that are then ingested •Colonization of surface of the host, followed by toxin production •Invasion of host tissues •Invasion Invasion of host tissues followed by toxin production “hit and run” versus persist Establishment of Infection Adherence Adhesins pili (fimbriae) Establishment of Infection Colonization (usually a mucous membrane) Compete with normal microbiota Obtain iron siderophores Avoid IgA shed antigens (ex. pili) (IgA protease) antigenic variation Y Y Y Y Y Y Y Y Y 2 6/10/2011 Establishment of Infection Delivery of effector molecules to host cells Type III secretion systems (injectisomes) Establishment of Infection Delivery of effector molecules to host cells Type III secretion systems (injectisomes) actin Invasion - Breaching the Anatomical Barriers Penetration of skin Penetration of mucous membranes Directed uptake by an epithelial cell injectisome 3 6/10/2011 Invasion - Breaching the Anatomical Barriers Penetration of skin Penetration of mucous membranes Directed uptake by an epithelial cell Exploitation of antigen-sampling processes Intestinal space (lumen) M P Invasion - Breaching the Anatomical Barriers Penetration of skin Penetration of mucous membranes Directed uptake by an epithelial cell Exploitation of antigen-sampling processes Avoiding the Host Defenses Hide within a host cell 4 6/10/2011 Avoiding the Host Defenses Hide within a host cell Avoid killing by complement proteins Gram-positives are protected by cell wall architecture Gram-negative - some are “serum resistant” Avoiding the Host Defenses Hide within a host cell Avoid killing by complement proteins Avoiding the Host Defenses Hide within a host cell Avoid killing by complement proteins Gram-positives are protected by cell wall architecture Gram-negative - some are “serum resistant” 5 6/10/2011 Avoiding the Host Defenses Hide within a host cell Avoid killing by complement proteins Avoid destruction by phagocytes Avoiding the Host Defenses Avoiding the Host Defenses Hide within a host cell Avoid killing by complement proteins Avoid destruction by phagocytes 6 6/10/2011 Avoiding the Host Defenses Avoiding the Host Defenses Hide within a host cell Avoid killing by complement proteins Avoid destruction by phagocytes Avoiding the Host Defenses Hide within a host cell Avoid killing by complement proteins Avoid destruction by phagocytes Figure 19.5 7 6/10/2011 Avoiding the Host Defenses Hide within a host cell Avoid killing by complement proteins Avoid destruction by phagocytes Avoiding the Host Defenses Hide within a host cell Avoid killing by complement proteins Avoid destruction by phagocytes Avoid antibodies Shed antigen (IgA protease) Antigenic variation Mimic “self” Damage to the Host Exotoxins (toxins) - toxic proteins produced by bacteria; often described according to their activity; neurotoxin, enterotoxin, cytotoxin Proteins Antigenic (vaccines can often be produced against them; toxoids) Heat-labile (generally) A B toxins (A subunit - active; B subunit - binds) A-B 8 6/10/2011 Examples of exotoxin-producing bacteria Examples of exotoxin-producing bacteria Examples of exotoxin-producing bacteria Clostridium tetani (neurotoxin) tetanus •obligate anaerobe, spore-former, soil, Gram-positive •disease scenario/characteristics •puncture wound → spores in tissue → germinate; vegetative cells multiply multiply, produce toxin •toxin - blocks inhibition of motor reflexes (blocks nerve transmission) → rigid contraction •treatment - antitoxin, antibiotics •prevention - vaccine; booster every 10 years 9 6/10/2011 Examples of exotoxin-producing bacteria Corynebacterium diphtheriae (cytotoxin) diphtheria Gram-positive rod, non-spore-forming, facultative Examples of exotoxin-producing bacteria Examples of exotoxin-producing bacteria Corynebacterium diphtheriae (cytotoxin) diphtheria •Colonizes throat •Toxin - inhibits eukaryotic protein synthesis → cell death •Local damage → pseudomembrane (dead cells, pus, blood) •Systemic damage - organs (ex. heart) •Lysogenic conversion •Treatment - antitoxin, antibiotics (but still 10% fatality) •Prevention - vaccine •kids - DTaP; then booster every 10 yrs. (Td) 10 6/10/2011 Endotoxin LPS (outer leaflet of Gram-negative outer membrane) Triggers toll-like receptors, initiating inflammation Localized - helps clear an infection Systemic - can lead to shock →dramatic drop in blood pressure, disseminated intravascular coagulation Heat stable No vaccine Damaging effects of the immune response Damage associated with inflammation repair process → scarring (ex. scarring of fallopian tubes → infertility) Damage associated with antibodies Antigen-antibody complexes (“immune complexes”) activate complement → inflammation Cross-reactive antibodies (i.e. bind to “self”) → autoimmune responses Example of a highly successful pathogen: Neisseria gonorrhoeae •causes gonorrhea •humans are the only host •does not survive in the environment •sexually transmitted Asymptomatic infections ~ 50% of infected women ~ 10% of infected men Gram-negative 11 6/10/2011 Example of a highly successful pathogen: Neisseria gonorrhoeae •causes gonorrhea •humans are the only host •does not survive in the environment •sexually transmitted Asymptomatic infections ~ 50% of infected women ~ 10% of infected men Example of a highly successful pathogen: Neisseria gonorrhoeae Pathogenesis •pili attach to mucosal surfaces hitch a ride on sperm? p •antigenic variation multiple genes that encode pili (other structures) •(IgA protease) Gram-negative •invades epithelial cells •appears to survive within neutrophils (PMNs) Example of a highly successful pathogen: Neisseria gonorrhoeae Damage •Inflammatory response ascend fallopian tubes → Pelvic Inflammatory y Disease (PID) scarring → infertility Gram-negative 12