Lecture 20

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Lecture 20
2010-11-12 00:12:01

Resistance to Pathogenic Microbes: General Features
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  1. 1. Defense is due to:
    • both non-specific (natural) and specific (immune) mechanisms.
    • Immunity enhances natural protective mechanisms and directs them to sites where needed.
  2. 2. Different microbes stimulate distinct
    lymphocyte responses and effector mechanisms (usually either humoral or cell-mediated). Patterns of evasion, virulence factors, and immunogenicity are different. Diverse systems and mechanisms are needed for elimination.
  3. 3. Survival and pathogenicity are a
    consequence of:
    a microbe's ability to evade or resist protective immunity. A variety of strategies have been devised to survive the powerful immunologic defenses.
  4. Disease and tissue injury may be due to:
    • host responses and products, rather than the microbe itself.
    • Immunity is necessary for host survival, but also has potential for causing damage to the host.
  5. Consider 4 groups of pathogens.
    Extracellular bacteria, intracellular bacteria, viruses, and parasites.
  6. Extracellular bacteria Disease is by two primary mechanisms:

    • 1) induction of inflammation;
    • 2) toxin production.
  7. Extracellular bacteria
    Natural resistance:
    Phagocytosis (neutrophils are most active), C' proteins, and macrophage TNF.
  8. Extracellular bacteria
    Immune response:
    • Primarily humoral; antibodies (Abs) to eliminate bacteria and neutralize toxins. Bacterial cell walls and capsules have many highly immunogenic T independent Ags. These may directly stimulate early IgM responses from B cells. Later, TH cells enhance Ab production and activate phagocytic and microbicidal functions of macrophages. IgM and IgG act as opsonins, activate C', and neutralize toxins. Negative consequences include the generation of disease-causing Abs:
    • e.g. Streptococcal sequelae diseases and autoimmune Abs due to polyclonal activation of B cells.
  9. Extracellular bacteria
    Evasion of the immune response
    is by mechanisms that favor tissue invasion (adhesive properties of bacterial surfaces, anti-phagocytic mechanisms, inhibition of C' activation, and genetic variation).
  10. Intracellular bacteria

    Some bacteria are able to survive intracellular killing by phagocytic cells (e.g. Mycobacterium tuberculosis and Listeria monocytogenes).

  11. Intracellular bacteria
    Natural resistance:
    The principle mechanism is phagocytosis, which is usually not effective.
  12. Intracellular bacteria
    Immune response:
    Major protective response is cell mediated immunity. IFN-g secreted by TH lymphocytes activates enhanced killing mechanisms of macrophages and increases phagocytosis. Host immune response is also the principle cause of tissue injury and disease.
  13. Intracellular bacteria
    Granulomatous inflammation
    occurs when activated macrophages collect locally and surround persistent microbes to prevent their spread. Tissue necrosis (death of cells due to injury) and fibrosis (scarring) may result. Fibrosis is a repair mechanism for tissue that cannot be replaced.
  14. Intracellular bacteria
    Evasion of the immune response
    is mostly due to the ability to resist elimination by phagocytes. M. tuberculosis and Legionella hemophilus inhibit phagolysosome fusion, while L. monocytogenes may form pores in phagolysosomes, inducing leakage of contents.
  15. Viruses
    Natural resistance:Two principle mechanisms are known.

    1. IFN production by infected cells, and 2. direct killing of virus infected cells by natural killer (NK) cells. These mechanisms are especially important in the very early course of viral infections (before the immune response develops).

  16. Viruses
    Immune response: A combination of 2 mechanisms.
    • 1. Specific Abs early in infection. Secretory immunity (IgA) is the basis for immunity to many viruses of the respiratory and GI tracts. This type of immunity is the target of oral vaccines. Humoral immunity also provides long-lasting protection after infections are cleared. Circulating immune complexes (Ag-Ab) may lodge in blood vessels and initiate C' mediated tissue damage.

    • 2. Cytotoxic T lymphocytes (TC) are the principle mechanism for combating established viral infections. Tc directly kill virus infected host cells and may be responsible for tissue injury in non-cytopathic virus infections. Molecular mimicry may induce immune responses to self Ags.

  17. Viruses
    Evasion of the immune response:
    Intracellular persistence is the most obvious mechanism. Viruses are also well-known for antigenic variation. Direct suppression of the immune response is noted with many viruses: e.g. HIV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV).
  18. Parasite
    (fungi, protozoa, and helminths): Important feature is chronicity (persistence over time).
  19. Parasites
    Natural resistance:Parasites are often well-suited to resist natural host defenses.
    • Many of the larval stages (that develop in invertebrate hosts) activate C' and are susceptible to intracellular killing by phagocytes, whereas the parasitic forms that develop in human hosts are resistant.

    • Many protozoa have a pellicle, fungi have cell walls, and worms may have a thick protective tegument.

  20. Parasites
    Immune response:Every type of response is known and observed. Some major ones include:
    • 1. Specific IgE and eosinophilia are elicited by many helminths (blood flukes and Trypanosomes). Enhancement of inflammation is an important anti-parasitic strategy.

    • 2. Cytokines from TH cells direct and modulate immune responses. A problem is that many parasites elicit inappropriate immune response. (Often an antibody response, which may not be very protective, is preferentially stimulated, instead of a T cell response which may be more protective).

    • 3. CTL's that kill host cells infected with intracellular parasites or directly attack helminths.

    • 4. Some parasites and/or their products induce granulomatous inflammation and fibrosis.

    • 5. Polyclonal B cell activation may be stimulated by parasite surface products, but could result in immune complex disease or production of autoreactive Abs.

  21. Evasion of the immune response:2 major groups of mechanisms. GROUP 1
    • 1. Parasites may reduce or alter their antigenicity.
    • A. Anatomic sequestration- Intracellular parasites, intestinal residence, formation of resistant cysts. However, these mechanisms are only temporary and partially effective.
    • B. Antigenic masking. Schistosoma mansoni larvae acquire a coating of host proteins.
    • C. Varying surface Ags. Some parasites change during their life cycle. The "variable surface glycoprotein." of Trypanosomes is coded by more than 100 different genes that can be plugged in like cassettes. Vaccine development is very difficult at best.
  22. Evasion of the immune response:
    2 major groups of mechanisms. GROUP 2
    • 2. Parasites may directly inhibit host immune responses.
    • a. Shedding of surface coats. This may occur spontaneously or after binding of Ab.
    • b. Surface molecules may breakdown or inhibit activation of C' proteins.
    • c. Inhibition of phagolysosome fusion.
    • d. Ectoenzymes that cleave bound Ab molecules.