Host Responses & Viral Evasion Flashcards
How will a (non-immune) cell typically respond to presence of a virus?
The Type I interferon response detects viral antigens using PRRs (eg RIG-1, PKR) and upregulate IFN-a/b synthesis (IRF > ISRE > transcription).
What is the effect of Type I IFNs on neary cells?
Cells activated by IFN-a/b will attempt to stop their protein synthesis to minimize viral replication should they be infected.
This is accomplished by JAK-STAT activation of PKR (phosphorylate elF-2a to inhibit translation) or OAS (activates RNAase L to digest any mRNAs).
How do viruses suppress the “anti-viral” state?
- Prevent the IFN binding (block the receptors or create decoys).
- Prevent elF-2a from being phosphorlyated (bind PKR, distract it with “decoy” elF-2a, or prevent its activation by sequestering dsRNA).
- Directly reverse the elF-2a phosphorylation.
What inflammatory cytokines are produced to mediate an immune response to viral infection?
TNF, produced by activated macrophages, CD4 T-cells, and NK cells, induces fever and can promote apoptosis.
IL-1b, produced by macrophages, is also a pyrogen.
IL-6 is another pro-inflammatory cytokine; not too relevant to this lecture.
How do viruses interfere with cytokine signaling?
Produce soluble TNF receptors, or IL-1b binding proteins.
Describe how NK cells normally contribute to fighting viral infections.
NK cells (and CTLs) kill cells that have been infected by viruses, noted by their display of viral antigen on MHC-I and NK activating ligands.
Note: They are actually downregulated by class I MHC (prevent errant killing), and activated by NK-activating ligands. They are also stimulated by INFs and IL-12.
How do viruses attenuate the function of NK cells and CTLs?
Upregulating HLA-C (inhibits NK), blocking the NK activators, as well as blocking the adhesion and costimulation involved in their activation (ICAM, B7).
How does the complement system fight viral infection?
Activated complement can tag targets (including viruses) for opsonization (b), and promote general inflammation (a). They can also form a lytic MAC pore.
Host cells express complement control proteins so they do not get targeted.
How do viral cells avoid the effects of the innate complement sytem?
Some encode homologs of the host complement control proteins. Others simply take host control proteins with them when they bud.
Summarize the process by which cells display viral antigen on MHC-I.
Degradation in the cytosol (usually by polyubiquitination > proteasomal degradation) yields peptides that are transported to the ER by TAP. With the help of accessory proteins like tapasin, they are “mounted” on MHC-I and then transported to the cell surface.
How do viruses interfere with MHC-I signaling?
- Degrade or block TAP to prevent viral antigen loading.
- Degrade MHC-I, or stop it from reaching the cell surface (retain in ER/golgi, direct to lysosomes)
- Downregulate MHC-1 expression.
What signals can induce a cell to apoptose?
External signals like Fas ligand or TNF.
Internal processes including p53 action and Bcl-2 inhibition causing release of cytochrome-c from the mitochondria and formation of the apoptosome and caspases.
How can viruses inhibit apoptosis?
- Block external apoptotic signaling (soluble TNF-receptor secretion).
- Inhibit p53.
- Encode anti-apoptotic homologs (eg Bcl-2)
- Inhibit caspases.
