Host Defenses & Viral Oncogenesis Flashcards
How does the innate immune system recognize viruses? What cytokines are secreted in Type I IFN secretion? Type II?
- PRRs (like TLRs: PKR, RIG-1)
- IFN∂, IFNß (activate NK cells); TNF∂, IL-1, IL-6
- IFN-gamma (via NK cells; INHIBITS TH2 RESPONSE), IL-2, IL-12
Why does a virus titer plateau in an immunocompetent patient after about 3 days? What ultimately eradicates the virus?
- Primary immune response: Type I IFN secretion
- T-cell mediated killing of infected cells (CTL goes to infection site via Th1 stimulation)
Why would you avoid using IFN-gamma to treat patients with viral infections?
too many side effects; causes flu-like symptoms
Describe how IFN∂ and IFN ß cause an immune response in virus-infected cells.
cell senses foreign nucleic acid via PKR, RIG-1, which causes a signaling cascade to activate IRF (TF), increasing IFN∂/ß transcription and release; this binds IFN∂/ß receptors on neighboring cells and stimulates (1) Jak/STAT pathway for those cells to secrete OAS & PKR (2) anti-viral state
Once the neighboring cell has IFN∂/ß R activated, what is the pathway of 1. PKR and 2. OAS.
activated receptor –> increase synthesis OAS & PKR
PREVENTING PROTEIN SYNTHESIS!!!
1. PKR phosphorylates dsRNA (TLR!!) and phosphorylates eIF2∂ to inhibit mRNA translation in the cell
2. OAS causes binds dsRNA (TLR!!) and synthesizes oligo-adenylate from ATP, which activates RNAase L (endoribonuclease); degrades mRNA
What is the anti-viral state? (4 things)
- increase MHC I expression
- increase PKR/inhibit protein synthesis
- increase OAS/mRNA degradation
- increase 2’-5’ synthase expression
Why do cells upregulate their activating ligands during a viral infection? What other cells upregulate activating ligands? What do MHC I receptors do when binding an NK cell?
- for NK receptors to bind for cell degradation
- cancer cells
- cause inhibition of degradation
During the adaptive immune response, MHC I Rs are upregulated to present viral Ag; What is the viral counterattack?
(a) inhibit/degrade TAP protein
(b) bind class I retroubiquitinase to degrade
(c) sequester MHC I in ER/Golgi
(d) downregulation of MHC I components
Apoptosis can be stimulated from within and from outside. Name 4 ways apoptosis can be stimulated exogenously.
- GFs: Fas, TNF∂
- Cells: NK cells, CTLs
What do viruses do to counterattack complement system?
b/c cells encode CD59, DAF and MCP that prevent MAC from inserting into own cells, viruses use these genes on cell surface as well [poxvirus, CMV, HIV]
What do viruses do to counterattack the apoptotic tendencies of host cells?
(a) virus-encoded TNF receptors to provide a TNF∂ sink
(b) inhibit caspases
(c) virus-encoded homologs of anti-apoptotic proteins, like Bcl2
(d) inhibit p53/Rb
Why is epitope mutation a good strategy in small viruses?
have small genomes with only a certain amount of proteins; more mutations cause more strains to evade the immune system [HPV, HIV, HSV, VZV]
Describe how viruses counter-attack a IFN∂ and IFN ß immune response? (2 ways)
(a) viruses encode viral IFN∂/ß binding proteins that have greater affinity for IFN∂/ß than do cellular receptors [poxvirus]; IL-1 binding protein to prevent fever [poxivrus]
(b) NS1 on influenza binds RIG-1
What are viral counterattacks for the PKR/OAS/eIF2∂ pathways? (4 ways)
(a) phosphatase that de-P eIF2∂ [herpesvirus]
(b) decoy RNA that binds PKR [adenovirus]
(c) decoy eIF2∂ that binds PKR [poxvirus]
(d) dsRNA binding proteins sequester dsRNA and prevent PKR activation [poxvirus]
What is the virus counterattack to upregulation of MHC I complexes?
(a) remove MHC I from surface but leave HLAC on surface
(b) “decoy” MHC I molecules [CMV]
(c) decrease activating ligand by sequestering/lysosomal degradation
(d) decrease adhesion molecules (ICAM-1/CD80/B7); less adherence means less chance of binding
