Supplemental Lecture (98/05/24 update) by Stephen T. Abedon (abedon.1@osu.edu)

  1. Chapter title: Viral Mechanisms of Pathogenicity
    1. A list of vocabulary words is found toward the end of this document
    2. Discussion of mechanisms of viral pathogenicity will be limited to the negative effects viruses have on individual cells, also known as cytopathic effects. Within this context we will discuss the cellular arm of the immune system, an important component in virus-mediated host damage.
  2. Cytopathic effects [CPE]
    1. Host cell damage:
      1. Cytopathic effects are damage to infected host cells caused by infecting viruses .
      2. Basically, viral infection can lead to cell abnormalities (biochemical and morphological) and/or cell death.
    2. Not exactly lysis:
      1. The damage defining cytopathic effects or death (cytocidal effects) is unlike that caused by lytic viruses upon the release of progeny virus .
      2. That is, lysis is a very purposeful killing of the host cell.
      3. Cytopathic effects instead are a consequence of the virus' metabolic needs and those of the host cell simply not completely corresponding.
  3. Cytocidal effects [noncytocidal effects]
    1. Deadly cytopathic effects:
      1. Cytocidal effects are cytopathic effects that lead to host cell death.
      2. Noncytocidal effects are cytopathic effects that do not lead to cell death.
  4. Syncytia [giant cells]
    1. Big cells:
      1. Syncytia multi-nucleated , giant cells formed through the fusion of host cells .
      2. Syncytia get large, are unwieldy, and, ultimately, die prematurely.
    2. For HIV , syncytia form because infected cells display viral adsorption proteins (i.e., envelope proteins ) on their surface. These bind to uninfected cells and cause plasma membrane fusion.
  5. Inclusion bodies
    1. Intracelluar granules:
      1. Inclusion bodies are intracellular granules whose presence is a result of viral infection .
      2. Inclusion bodies do not necessarily represent accute virus-induced damage of host cells, but instead can be a more benign effect.
    2. The characterization of inclusion bodies is useful for the identification of some viral infections .
  6. Cell-mediated immunity
    1. Destruction of virus infected cells:
      1. Virus infected cells may be recognized by the immune system, which leads to the destruction of the virus infected cells.
      2. This immune system action is a very important mechanism by which viral infection can lead to cytopathic, particularly cytocidal effects.
      3. Significant host damage can result from the effects of cell-mediated immunity.
    2. Various mechanisms:
      1. The various mechanisms (two general mechanisms) by which the destruction of virus-infected cells is mediated are termed cell-mediated immunity.
      2. Mechanisms of cell mediated immunity involve the distinguishing of virus infected cells from uninfected cells through the recognition of viral proteins found associated with the cell
      3. These proteins are recognized by separate mechanisms leading to the distinguishing of these cell-mediated immunity into two distinct mechanisms:
      4. those in which viral proteins are recognized by soluble antibody
      5. those in which viral proteins are recognized by something other than soluble antibody
  7. Antibody-dependent cellular cyotoxicity [ADCC, natural killer cells]
    1. Antibody tagged cell destruction:
      1. Mechanisms of cell-mediated immunity in which viral proteins are recognized by soluble antibody are termed antibody-dependent cellular cytoxicity (or ADCC).
      2. ADCC is mediated by natural killer cells.
    2. Mechanism:
      1. ADCC is a consequence of three distinct steps:
      2. viral proteins find their way to the surface of infected cells as a consequence of membrane proteins being left behind in the infected-cell membrane following either adsorption or budding
      3. these proteins are recognized as foreign by the body and antibody is produced which recognizes (i.e., binds) these proteins
      4. natural killer cells recognize the presence of antibody bound on the surface of cells; they then follow an evolutionary algorithm which goes something like this:
        1. a cell to which an antibody is bound is either not-self, or is self but infected by a pathogen
        2. destroy that cell in order to interupt pathogen replication
  8. Cyototoxic T cell-mediated immunity [major histocompatibility complex, MHC, cytoxic T lymphocyte, CTL]
    1. Antibody independent:
      1. In contrast with ADCC, cytotoxic T cell-mediated immunity is not a response to soluble antibody binding.
      2. In fact, cytotoxic T cell-mediated immunity is a mechanism by which cells harboring foreign proteins, but not displaying those proteins intact on their surface, may be recognized and targetted for destruction.
    2. Mechanism:
      1. Cytoxic T cell-mediated immunity occurs via the following steps:
        1. all of the proteins produced in a cell are ultimately targetted for destruction and broken down; partially broken down intracellular proteins are sequestered by vesicle manipulating machinery and brought into contact with major histocompatibility complex (MHC) proteins made by the host
        2. in conjunction with the MHC proteins these protein fragments are displayed on the surface of cells.
        3. white blood cells called cyotoxic T cells (or cytotoxic T lymphocytes or CTLs) are capable of reversibly interacting with surface-presented MHC proteins.
        4. recognition is said to occur if strong interaction with the MHC protein-foreign protein fragment occurs:
          1. the immune system efficiently culls CTLs capable of recognizing host proteins displayed by MHC proteins
          2. as a consequence, the host CTL populations tend to be much more capable of recognizing foreign proteins displayed by MHC proteins than they are of recognizing proteins normally produced by host cells
        5. upon sufficiently strong binding, the CTL is induced to effect the destruction of the host cell
        6. in this way, host cells displaying (sufficiently) aberrant proteins may be eliminated, thus interfering with viral replication and propagation
  9. Latent infection
    1. Selection against viral protein synthesis:
      1. The net effect of cell-mediated immunity is to strongly select against the synthesis of virus proteins and the release of virus progeny.
      2. For many viral infections this selection is sufficient to markedly reduce viral replication and allow the clearance of the infection.
      3. That is, one mechanism through which an individual may recover from a virus infection is via the destruction of virus-infected cells through the action of cell-mediated immunity.
    2. Lack of clearance:
      1. For some viruses, however, this selection simply results in a predominance of latent forms, ones which are neither replicating nor translating proteins.
      2. Thus, some viral infections can become latent, only to re-emerge upon immunodepression.
      3. Whether they do so depends both on the body's response to the viral infection (timing, intensity) and the type of virus infecting (i.e., most animal viruses are not capable of initiating a latent infection).
  10. Vocabulary
    1. ADCC
    2. Antibody-dependent cellular cytotoxicity
    3. Cell-mediated immunity
    4. CPE
    5. CTL
    6. Cytopathic effects
    7. Cytocidal effects
    8. Cytotoxic T cell mediated immunity
    9. Cyotoxic T lymphocyte
    10. Giant cells
    11. Inclusion bodies
    12. Latent infection
    13. Major histocompatibility complex
    14. MHC
    15. Noncytocidal effects
    16. Syncytia
  11. Practice questions
    1. How does a non-cytocidal effect differ from cytopathic effects, such as those induced by cell-mediated immunity? [PEEK]
    2. For over a year a virus has been infecting a lymphocyte which is circulating in the blood. The host organism is immunologically competent and, in fact, other viruses of the same type were cleared from the host by cell-mediated immunity many months previously. Other than the fact that the virus is obviously infecting latently, what definite thing can you say about the interaction of the virus genome and its host cell's biochemistry?[PEEK]
    3. Multi-nucleated cells formed through the fusion of virus-infected host cells with other host cells are called __________? (one word answer) [PEEK]
    4. A viral effect that leads to cell death is called? (choose best answer) [PEEK]
      1. cytopathic effect
      2. formation of inclusion body
      3. syncytial effect
      4. cell-mediated effect
      5. cytocidal effect
      6. natural killing effect
    5. Define cytopathic effect. [PEEK]
    6. A virus which damages its host cell, especially visibly, but not to the point of killing it is said to be displaying __________ effects. [PEEK]
    7. What are three terms or mechanisms associated with the viral pathogenicity of individual cells, particularly which are associated with the presence or absence of host cell morbidity or mortality. [PEEK]
    8. What are syncytia and how do they form? [PEEK]
    9. Major Histocompatibility Complex proteins are associated with a form of immunity mediated by what kind of white blood cell (i.e., what kind of lymphocyte)? [PEEK]
    10. Destruction of virus-infected host cells can follow the presentation of virus antigen by MHC and subsequent recognition by cytotoxic T lymphocytes, or via the attraction of natural killer cells to __________ bound to virus proteins found on the surface of infected host cells. [PEEK]
    11. Syncytia are __________. [PEEK]
    12. Syncytia formation is associated with (circle only one correct answer) [PEEK]
      1. HIV infection
      2. carbuncles
      3. bacterial meningitis
      4. botulism
      5. all of the above
      6. none of the above
  12. Practice question answers
    1. A non-cytocidal effect does not, by definition, lead to infected cell death. The effect of cell-mediated immunity is infected cell death.
    2. The virus is not making any protein, or at least none recognized by host cytotoxic T cells.
    3. Syncytia
    4. v, cytocidal effect
    5. The damage a virus does to a host cell it is infecting.
    6. non-cytocydal cytopathic (effects)
    7. cytopathic, cytocidal, non-cytocidal, cytotoxic T cell mediated immunity, cellular immunity, antibody dependent cellular cytotoxicity, syncytia, etc.
    8. Syncytia are large, multinucleated cell formed by the fusion of more than one smaller cell. This can occur when viral envelope proteins are present on the surface of a virus infected cell, and that virus infected cells collides with an uninfected cells displaying viral receptor molecules on its surface. That is, the infected cell, acting effectively as a giant enveloped virus, can fuse with the uninfected host cell. Syncytia are a form of viral cytopathic effect. They can lead to cell death so therefore may be regarded as a potentially cytocidal effect.
    9. Cytotoxic T cells
    10. Antibodies
    11. large, multinucleated cells that are generated through the fusion of normal size cells, often as a consequence of viral infection; syncytia are fragile and not as durable as regular cells
    12. i, HIV infection
  13. References
    1. Black, J.G. (1996). Microbiology. Principles and Applications. Third Edition. Prentice Hall. Upper Saddle River, New Jersey. pp. 406-407, 498-500.
    2. Tortora, G.J., Funke, B.R., Case, C.L. (1995). Microbiology. An Introduction. Fifth Edition. The Benjamin/Cummings Publishing, Co., Inc., Redwood City, CA, pp. 400-405.