Human Innate Immune Responses to Viruses

Human Innate Immune Responses to Viruses

1. 3 Mechanisms to Recognize Pathogens (PRRs)

   • 1. Detection of signals produced by tissue damaging infections
     • signals trigger pro-inflammatory responses by DCs
   • 2. Detection of Missing Self
     • NK cells constantly monitor presence & conformation of MHC I molecules (present in all cells)
   • 3. Detection of pathogens thru PaSern Recognition Receptors (PRRs)

2. Pattern Recognition Receptors (PRRs)

   • recognize non-self, mainly PAMPs (pathogen associated molecular patterns
   • TLRs (Toll-like Receptors)
     • transmembrane proteins & recognize diferent PAMPs; subgroup of PRRs
     • TLR4
       • recognizes LPS in Gram negative bacteria
     • TLR3/7/8/9
       • TLR3: dsRNA
     • Cytoplasmic PRRs
       • NOD like receptors: recognize endogenous microbial molecules & result in activation of inflammatory responses via caspases
       • RIG-I-like receptors: recognize intracellular dsRNA or ssRNA. RNA helicases that recruit cellular co-factors thru CARD domains. recruitment results in interferon cascades activation

3. Cytokines

   • small regulatory proteins that act as signaling molecules
     • early in infection, macrophages 1st produce cytokine to attract WBCs)
   • Types of Cytokines
     • Hematopoietins
       • mainly involved in red blood cell production
       • Tumor Necrosis Factors (TNFs)
         • cause cell death of infected cells
         • Chemokines
           • attract other WBCs to site of infection
           • Interleukines (IL)
             • produced by WBCs, CD4+ T cells & monocytes. involved in development & differentiation of lymphocytes
             • Interferons
               • cause of antiviral state, activates immune cells, promotes antigen presentation & increase ability of healthy cells to resist virus infection
                 • Type 1: alpha & beta. responsible for antiviral state
                   • Type 2: gamma. produced later & in response to other stimuli. synthesized by NKs, NKTs, CD4, & CD8 T cells

4. Interferons

   • response is rapid (w/in hours) & important for pre-specific immune response
     • Bind to neighboring cells to their cellular receptor
       • Causes phosphorylation signaling cascade resulting in:
         • Decrease protein synthesis: eIF2 phosphorylation (no protein synthesis initiation)
         • Activation of Rnase L: destroys cellular & virus RNA
         • Activation of interferon stimulated genes (ISGs): involved in limiting crucial steps for virus replication (restriction factors)
         • Increase antigen presentation (increases MHC 1 & 2 molecules on cell surface & immunoproteasome function)
         • Activation of apoptosis, esp. in infected cells
   • Interferon-stimulated Genes (ISGs)
     • can block specific steps in virus replication at different levels
       • Entry
         • MX1, MX2, CH25H, IFITMs, TRIMs
       • Replication & gene expression
         • ZAP, IFIT, OAS-RNaseL, ISG15, APOBEC
       • Exit
         • Viperin, Tetherin/BST2
   • ISGs: Blocking Entry