Host Responses to Viral Infection

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					Host Responses to Viral
       Infection
 How do host cells fight back?
How do host cells fight back?
 Host cells don’t just sit and passively allow the
    virus to take over their metabolic machinery –
    they fight back
   The immune system defends the host against
    infection by viral invaders.
     There are two types of host response to virus
      infection
         Innate response which involves
           Phagocytic cells
           Interferon
           Natural killer cells
        Adaptive response which involves
           T lymphocytes (T cells)
           B lymphocytes (B cells)
           MHC class I and class II molecules
How do host cells fight back?
 Innate defenses
   Phagocytic cells
      Include neutrophils (polymorphonuclear leukocytes
       - PMNs) and macrophages
      Phagocytic cells may engulf viruses and take them
       up into phagosomes.
      When the phagosomes fuse with lysosomes, the
       lysosomal enzymes may or may not destroy the
       virus.
Mechanism of phagocytosis
How do host cells fight back?
 Innate defenses
    Eukaryotic cells produce interferon
        Interferon is host specific, not virus specific (reason will be clear
         later on)
        Can be produced by virtually any cell
        May be induced by viral infection (RNA viruses are better inducers
         than DNA viruses), ds RNA molecules, intracellular bacteria like
         Rickettsia, Gram-negative endotoxin, and metabolic inhibitors of
         protein synthesis
        Interferon is a first line of defense against viruses before a specific
         immune response is mounted
        There are three different classes of interferon (IFN) - , , and ;
             and  are called type I interferon and they function mainly in
             inducing cells to become resistant to viral infections
             is called type II interferon and it functions to mainly to modulate the
             immune response
How do host cells fight back?
    Types I and II IFN cause the following biological effects:
        Both types cause an activation of macrophages, natural killer
         cells, cytotoxic T lymphocytes, and modulation of the synthesis
         of antibodies
        Both types induce increased MHC class I expression.
        Both types induce a fever.
        Both types cause an inhibition of cell growth and are effective
         in the treatment of some tumor cells.
        Type II induces increased class II antigen expression as well as
         Fc receptor expression
        In type I treated cells, and to a much lesser extent in type II
         treated cells, there is an inhibition of viral replication.
             Interference with penetration and uncoating, or assembly
              (mechanisms are unknown).
             Interference with viral transcription - due to a host protein
              known as Mx, which is induced by interferon
             Interference with viral mRNA translation
How do host cells fight back?
    The mechanism that activates type I interferon production is as
     follows:
        The regulatory sequence for IFN shows three functional domains
        Two domains bind positive regulatory molecules (gene activators)
        One domain binds a repressor protein that blocks transcription.
            The protein is labile and anything that inhibits protein synthesis
              results in the protein not being replenished.
            When this happens, the two positive regulatory proteins get
              phosphorylated.
            They bind to the two sites upstream from the empty repressor site
              to activate transcription and interferon is made.
            The mRNAs that are made have destabilization sequences and
              have short half-lives.
How do host cells fight back?
How do host cells fight back?
    What is the action of interferon?
       Interferon prepares cells to combat viral infection, if
        necessary.
       Interferon is secreted from an infected cell and must
        bind to a cellular receptor on the plasma membrane of a
        neighboring cell ( this accounts for the species
        specificity) to induce an anti-viral state in the cell.
           Both  and  IFN bind to a common receptor
            IFN binds to a different receptor
           The species specificity of interferon is due to the
            specificity of the action of the IFNs with their
            receptors.
How do host cells fight back?
IFN activity
      Binding triggers a signal transduction cascade.
      A message is sent through this cascade which involves
       protein kinases and transcription factors. This leads to
       the induction of the transcription of several different
       genes. Cells that have been induced by interferon:
          Express new membrane associated surface proteins
          Have altered glycosylation patterns
          Express at least three proenzymes that, when
           activated, function to inhibit viral mRNA translation:
IFN activity
Interferon
          The first proenzyme is oligoisoadenylate synthetase (OS).
           It catalyzes the formation of a 2’-5’ adenylic acid oligo (2’-
           5’ oligo A) instead of an an oligo with the conventional 3-
           ’5’ phosphodiester linkage.
          When the virus comes in dsRNA provides the signal for the
           proenzyme to be activated to the functional enzyme.
          2’-5’ oligo A is made
          2’-5’ oligo A activates a second proenzyme, RNAse L which
           cleaves both both viral and host cell mRNA, thus inhibiting
           translation for both
          This is more effective against RNA viruses. What does the
           DNA virus need to do to activate this enzyme?
The antiviral state
Antiviral activity
Interferon
          The third enzyme is protein kinase RNA dependent (P1 or
           PKR)
          When the virus comes in dsRNA provides the signal to
           activate the enzyme. The enzyme first catalyzes the
           addition of a phosphate to itself (self-phosphorylation)
          Next the phosphorylated enzyme phosphorylates the 
           subunit of eIF-2.
          This blocks the GDP/GTP exchange necessary for
           reutilization of the  subunit in translation initiation.
          Thus translation of both host and viral mRNAs ceases.
          There is some discrimination between viral and host mRNA
           via localization of the activity to the site of dsRNA. This is
           also true for the OS system.
The antiviral state
Antiviral activity
How Does PKR Really Work?

   The host cell enzyme that phosphorylates eIF2 is
    called protein kinase RNA dependent (PKR).
   PKR is synthesized as an inactive proenzyme that
    must be phosphorylated in order to become active.
   The trigger for phosphorylation is ds RNA which is
    produced not only when RNA viruses express their
    genomes, but also when DNA viruses transcribe from
    both strands in the same location in their genome,
    producing complementary RNA molecules that can
    base-pair with each other.
How does PKR Work?

   When two PKR proenzyme molecules bind to
    dsRNA, each undergoes a conformational
    change that cause it to phosphorylate the
    other PKR molecule.
   The activated PKR molecules than attach
    phosphates to eIF-2 proteins.
How does PKR Work?
Inhibition of Eukaryotic Protein Synthesis
Interferon
 What countermeasures do viruses have to
  combat the host interferon system defenses?
   Reovirus has a core protein that binds to dsRNA to
    prevent its activation of the PKR system
   Adenovirus VA1 protein also prevents dsRNA from
    binding to PKR
   Poxvirus encodes a protein that binds to dsRNA and
    blocks activation of both the PKR and OS proenzymes
How do host cells fight back?
 Innate defenses
   Natural killer (NK) cells – NK cells are large, granular
    lymphocytes that are activated by three types of
    targets:
      Antibody coated cells
      Cells infected by viruses and some intracellular bacteria
      Cells lacking class I MHC molecules. NK cells express
       inhibitory receptors that recognize class I MHC molecules,
       and therefore NK cells are inhibited by class I expressing
       cells and activated by target cells lacking class I molecules.
       Some viruses are known to down regulate expression of
       class I molecules.
      Activated NK cells lyse the target cells by releasing granules
       that contain perforin that creates pores in the target cells
       and granzymes that enter the target cells through the pores
       and induce apoptosis of the target cell.
NK activity
NK activity with normal cell
NK activity with cell lacking MHC
class I molecules
How do host cells fight back?
 Adaptive responses
   B cells have structures on their surface called
    antibodies or the B cell receptor (BCR) that recognize
    and bind to foreign antigens (more specifically
    antigenic determinants or epitopes).
   Similarly, T cells have structures on their surface
    called T cell receptors (TCR) that recognize and bind
    to foreign epitopes.
      Each B or T cell has many identical BCRs or TCRs on its
       surface and they all recognize the same epitope.
      Different B or T cells have different BCRs or TCRs and each
       recognizes its own unique epitope.
      The epitopes recognized by BCRs are peptides, nucleic acids,
       or polysaccharides and they can be recognized in solution.
      The epitopes recognized by TCRs are peptides and they can
       only be recognized in the context of a self antigen (More on
       this later).
How do host cells fight back?
  Binding of a BCR to its epitope will cause that B cell
   to proliferate and differentiate into a plasma cell that
   will secrete antibodies of the same specificity that
   was on the surface of the original B cell.
  Binding of a TCR to its epitope will cause that T cell to
   proliferate and differentiate into an effector cell that
   will be responsible for a type of immunity that can kill
   infected cells.
      Some effector cells have CD4 ( T helper cells) on their
      surface and some have CD8 (cytotoxic T cells) on their
      surface.
How do host cells fight back?
  The TCR can only recognize and bind to its specific
   epitope if that epitope is associated with a self MHC
   (major histocompatability) molecule.
     There are two basic types of MHC molecules
        Class I MHC molecules are found on the surface of all
         nucleated cells.
            Class I molecules present peptides made inside the cell to
             CD8 +cytotoxic T cells.
            The class I molecule with its associated peptide is
             recognized and bound by both the TCR (recognizes the
             peptide in conjunction with the MHC class I molecule) and
             the CD8 molecule.
            The interaction triggers the CD8+ cytotoxic T cell to cause
             the infected cell to undergo apoptosis
MHC Class I Interaction with
CD8+ T Cell
Presentation of Foreign Antigen Made
Within the cell to CD8+ T Cells
Killing by cytotoxic T cell
How do host cells fight back?
        Class II MHC molecules are found on the surfaces of cells
         of the immune system, including B cells and macrophages.
        Class II molecules present peptides made outside the cell
         to CD4 + helper T cells.
        The class II molecule with its associated peptide is
         recognized and bound by both the TCR (recognizes the
         peptide in conjunction with the MHC class II molecule) and
         the CD4 molecule.
        The interaction triggers the CD4+ helper T cell to release
         cytokines that help B cells to proliferate and differentiate
         into plasma cells that secrete antibody of the same
         specificity that was on the surface of the original B cell.
MHC Class II Interaction with
CD4+ T Cells
Presentation of Foreign Antigens Made
Outside the Cell to CD4+ T Cells
MHC Class II Interaction with
CD4+ T Cells
How do host cells fight back?

 How do antibodies effect viruses?
   Antibodies may directly neutralize viruses by
    preventing their binding to their host cell
    receptor.
   They can indirectly inactivate or neutralize the
    virus by signaling other mediators (phagocytic
    cells and complement) that inactivate the
    virus.

				
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