Viral Pathogenesis Intro and Adeno Flashcards
Host detection of viral RNA
- cytoplasmic and endosomal RNA sensors
- dsRNA/ssRNA sensors include PKR, RIGI, MDA5
- endosomal receptors are TLR3/7
Virus Disease (2 factors)
- direct effects of virus on cells, tissues, organs
2. Indirect effects (immune mediated)-host response can be harmful
Host Detection of viral RNA and IFN induction
- interaction of RNA w/ RNA sensors activates TFs (IRF3, NF-kappaB)
- TFs induce Tc of type 1 IFNs
Host Cell Detection of viral RNA through PKR and translational inhibition (dsRNA)
- dsRNA activates PKR
- PKR undergoes autophosphorylation, dimerizes and phosphorylates eIF2alpha
- phosphorylated eIF2alpha binds eIF2B
- inhibition of translation initiation
-dsRNA activation of 2’5 oligo adenylate synthase
-enzyme produces a chain of adenines linked 2’5
causes dimerization of RNase L, chews up RNA in cell
Host Detection of viral DNA
- if DNA is replicating in cyto will be recognized as foreign-DNA is only in nucleus
- pox are large DNA viruses, lots of machinery needed for rep, rep in cyto
- DNA recognized by cGAS, which produces cGAMP
- activates IRFs and NF-kappaB
Viral Defense against host defense
-blocking innate response
Viral homologues of
- Fc receptors
- IFN alpha, gamma, beta
- TNF receptors
- cytokines
- MHCI-secreted and compete for binding
- complement interference
- interference of Ag presentation by MHCI
Viral Blockers of Ag presentation by MHC1
HIV tat, adeno E1A block MHC gene Tc
hCMV US11, US2 enhance proteososme degradation of MHC
HSV ICP47, EBV EBNA interferes w/ TAP
Adeno E3 19K protein (4)
- retains class I MHC molecules in ER blocking presentation of antigenic peptides to CD8 T cells
- membrane glycoprotein expressed by all Ad serotypes (except A and F)
- N terminal lumenal domain assoc. w/ lumenal domain of MHC1 molecules
- C terminal cytosolic tail block transport of MHCI molecules to cell surface through ER retention motif
Adeno E3 14.7 K protein (4)
- inhibits TNF alpha mediated cytotoxicity
- blocks ligand induced TNFR1 internalization, preventing DISC formation
- inhibits recruitment of FADD, TRADD, caspase 8 to death domain
- E3 promoter also contains NF-kappaB binding site, which is activated by TNF alpha
Adeno E3 10.4 K and 14.5 K proteins
E3-10.4K (RID alpha) and 14.5 K (RID beta) proteins assoc. to form receptor internalization complex (RID)
- accelerates clearance of Fas and TRAIL receptors from cell surface
- inhibits inflammation and apoptosis
VA RNAs
- act as dsRNA decoys bind and inactivate PKR
- may also act as miRNAs to modulate host gene expression
- the complex secondary structure of VA interferes w/ the rxn, stopping phosphorylation and dimerization
EIA region
- drive cells into S phase to favour vrep
- inhibits MHCI Tc
- causes redistribution of histone acetyltransferases which regulate Tc (p300/CBP)
- inhibits p53 mediated Tc activation
