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Microbial Pathogenesis

Microbial Pathogenesis. October 18, 2011 by David E. Briles dbriles@uab.edu 934-6595. Whether a pathogen is able to cause symptoms (disease) is dependent on the interaction of the pathogen with the host. This interaction is called Microbial Pathogenesis .

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Microbial Pathogenesis

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  1. Microbial Pathogenesis October 18, 2011 by David E. Briles dbriles@uab.edu 934-6595

  2. Whether a pathogen is able to cause symptoms (disease) is dependent on the interaction of the pathogen with the host.This interaction is called Microbial Pathogenesis.

  3. Innate immunity & antigen-specific adaptive immunity Microbial virulence mechanisms (mediated byvirulence factors) Protects against pathogens and tumors Allows the pathogen to evade immunity, survive in the host, and spread to others Bacterial Pathogenesis How do these opposing forces stay in balance?

  4. Understanding Microbial Pathogenesis leads to: • New anti-microbial drugs (antibiotics) • New and improved vaccines • Use of cytokines to stimulate innate immunity • Better supportive therapy • New preventive measures

  5. Disease Symptoms • generally are the result of inflammation caused by host response to the pathogen. • can be caused by toxins of the pathogen that damage the host. • can be caused by chronic infection that leads to erosion and destruction of host tissue and sometimes whole organs. What is the importance of disease symptoms?

  6. Antibiotics • Originally from natural products(selected in nature from the competition between microbes). • Antibiotics block essential microbial-specific functions.(DNA replication, protein synthesis, cell wall synthesis etc.) • Antibiotic resistance is the result of mutations and gene exchange which lead to new variants of the original pathogen. • Future antibiotics will exploit new targets identified by studies of microbial pathogenesis.

  7. In vivo studies of microbial pathogenesis are conducted by • Administering of drugs, cytokines, antibodies or gene products that target specific suspected bacterial or host mechanisms. • Genetic knock-out mutants in, • the host (innate immune factors, adaptive immunity, cell receptors) • the pathogen (virulence factors)

  8. Attributes of a Pathogenic Microbe • Acquisition by a host • Exploitation of a host niche environment • Usually this niche is in sterile tissue (otherwise it would generally not cause disease symptoms) • Evasion of host defenses (usually partial) • Multiplication in the host • Produce disease symptoms • Transmission to others

  9. Attributes of a Pathogenic Microbe • Acquisition by a host • Exploitation of a host niche environment • Usually this niche is in sterile tissue (otherwise it would generally not cause disease symptoms) • Evasion of host defenses (usually partial) • Multiplication in the host • Produce disease symptoms • Transmission to others

  10. The evolutionary success of a pathogen is measured by its ability to infect or colonize additional hosts, not in its ability to kill.

  11. All pathogens have developed ways to be transferred to others, and most have evolved to keep the host alive for a long enough to maximize their ability to pass to other hosts.

  12. Some pathogens such as HIV, which causes AIDS, do not have to be transmitted efficiently. They have figured out how to remain in a host long enough to maximize their chance to be passed to others before the original host dies.

  13. Pathogens such as Vibrio cholera(or Anthrax) don’t mind killing their host because in doing so they produce enough bacteria in a watery diarrhea (or spores on the savanna) to guaranty their transmission to a new host.

  14. Major Host Defenses Mechanical Barriers skin epithelial cells mucus cilia stomach acid proteases, etc Phagocytes macrophages kupffer cells granulocytes Pattern Recognition Receptors Toll-Like-Receptors (TLR) C-reactive protein Mannose-Binding Lectin Complement Cytokines Interferon a, b, g TNF-a, b, IL-1, IL-2, IL-4, IL-6, IL-17, etc. Antibody IgM, IgA, IgG, IgE T-Cells CD4, CD8 NK-Cells

  15. Phagocytes (PMN & Macrophages) • Ingest and destroy microbes • Find microbes by: • Chance encounters • Chemotaxis • bacterial breakdown products (N-formyl methionine) • complement fragments (C5a) • leukotriene from stimulated lymphocytes • Recognize microbes by molecules on their surface • Deposited complement (C3b) • Antibody Fc • Repeating structures on microbe surfaces (manose-binding lectin)

  16. Protective Action of Antibody • Alone • blocks adherence • blocks toxin activity • blocks enzymatic activity • In conjunction with complement • aggregates and opsonizes toxins • aggregates and opsonizes microbes • blocks enzymatic activity • lyses host cells bearing bacterial or viral antigens • (containing bacteria or viruses) • lyses Gram-negative bacteria

  17. Membrane Attack Complex (MAC)

  18. Complement’s role in opsonophagocytosis • C3 is activated • through the alternative pathway (factor B) by many microbial • surfaces. (Extracellular pathogens generally inhibit this pathway). • through the classical pathway (C1q) by IgG and IgM antibody • bound to pathogen surfaces. • through a lectin pathway (mannose binding protein, L-ficolin, etc. ) • C3 activation and surface deposition mediates • chemotaxis (C5a) • opsonization (C3b, iC3b) • lysis {membrane attack complex (C5b, C6, C7, C8, C9)}.

  19. Cytokines • provide communications between immune cells • activate (or inactivate) immune cells • can stimulate protection against microbial infections • can restore tissue to a non-inflammatory state as an infection subsides • mediate many of the inflammatory symptoms of infectious disease.

  20. Recognition of Pathogens is facilitated by PRRs which recognize PAMPs • PRR = Pattern Recognition Receptors • family of TLRs (toll-like receptors) • C-reactive protein • Mannose-binding lectin, etc. • PAMP = Pathogen-Associated Molecular Patterns • Cell walls of bacteria • LPS of bacteria • Flagella of bacteria, • Microbial DNA and RNA, etc.

  21. TLR4 is a PRR that recognizes LPS • Gram negative bacteria all make LPS • Mutant mice that lack TLR4 are much more susceptible to most gram negative bacteria. • Yersinia pestis causes plague • Y. pestis makes normal LPS in the flea (insect host) • Y. pestis makes a variant LPS in mice to escape recognition by TLR4 • Mutants that make normal LPS in mice are totally avirulent.

  22. Helper (CD4) T cells: • Activate (help) B cells to make antibody • Mediate cell-mediated immunity • Enhance production of cytotoxic T cells • Activate macrophages to kill intracellular bacteria, and destroy infected host tissue.

  23. Inflammation, enhances microbial killing, often at the expense of host tissue

  24. Two types of pathogenic bacteria • Extracellular-- replicate outside of cells and must therefore avoid being killed by phagocytes or complement. • Intracellular -- replicate inside cells and must therefore avoid being killed inside phagocytes by the antibacterial properties of lysozomes.

  25. Extracellular Bacteria • Host Resistance mediated by: • Antibody • Complement • opsonization of all bacteria • lysis of gram negative only • Phagocytes • Pattern Recognition Receptors • TLRs, mannose binding proteins, etc.

  26. Ten Minute Break

  27. From the Perspective of the Pathogen(Just looking for a warm damp place to live)

  28. The special properties that allow pathogens to survive, spread, and cause disease are calledVirulence Factors

  29. Virulence Properties • Exploiting a particular niche • Adherence to host tissues • Partial (or complete) escape from host immunity • Protects itself from Ab and C' attack • Invasion into cells & avoidance of degradation in lysozomes • Interference with host and/or adaptive immunity • Live in protected tissue sites • Means of acquiring nutrients • Enzymes, siderophores, and transport machinery • Mechanism for transmission to the next host

  30. Adherence by many pathogens is important because, • It prevents them from being cleared by mucus flow. • It is necessary to subsequent to tissue and cellular invasion. • Presence on the mucosa is frequently critical for transmission.

  31. Bacterial Toxins • Exotoxins -- secreted molecules that can kill, damage, or alter host cells • Diptheria toxin • cholera toxin • tetanus toxin, etc. • Endotoxins -- Lipopolysaccharides (LPS) in the outer membrane of gram negative bacteria

  32. Bacteria get iron via • Siderophores(secreted molecules that bind iron ions) • Transport of siderophore+Fe+++ • Cytoplasmic degredation siderophore-Fe+++ to release Fe+++ • Transport of iron-binding transferrin, lactoferrin or heme. • Growing intracellularly (where iron is more readily available)

  33. Regulation of Virulence Factors in Response to Host Conditions • Temperature • Carbon source • Concentration of Iron, Manganese, or Calcium • Osmolarity • pH • Stress

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