I. interferons-cytokines both type 1 and 2 detect viruses→ transcription and translation of other cytokines, inflamm. Mediators(IL-12 and IL- 6)
• A. Type 1 interferons
o i. Interferon-alpha and interferon-beta
o recognize just viral motifs inside a cell
o viral motifs in cytoplasm(if cell is infected)
o in vacuoles(in uninfected dendritic cells) interact w/ TLR-7,8,9,3
*IFN-β: TLR 3 only rest with IFN-α
• b. Type 2 interferon
o i. interferon-gamma
o similar in action to type 1 IFNs but also recognizes other intracellular pathogens besides viruses
II. effects on interferons expression of inflammatory cytokines
IFN recognition triggers Jak-Stat pathway = phoshorylation cascade -> release of cytokines like: IL-1, TNF, IL-6, IL-12 => anti-viral enzymes
Expression of anti-viral enzymes
• A. halting protein production
o Transcription: mRNA
• Rnase:destroys RNA
-RNase L: degrades mRNA and rRNA
o Translation: amino acid chain
• PKR (imitation factor protein): protein that disables cell’s own initiation factor (stopping initiation of translation)
• B. halting viral budding from host cell
**FOR both RNase L, PKR to work they need dsRNA
o Mx proteins stop blebs of cell membranes from pinching off
* Budding: virus pushes off of surface awm ay frohost cells and does not kill the host
• C. viral evasion of interferon effects
o Flu virus covers dsRNA w/ a protein
o So dsRNA not detected
o Poxviruses- stop phsophorylation cascade (Jak-Stat pathway) that→ antiviral gene expression
• D. Interferons as disease treatments
o INF-gamma used to treat hepatitis B&C(viral infection that can cause cancer)
***1. Virally-caused cancers: ex: Kaposis Sarcoma—caused by HIV
III. Induction of apoptosis
a. p53 pathway
*phosphorylation cascade
*results in mitochodrial release of ions and proteins that lead to cell death through apoptosis
*can be stimulated by external signals
OR
triggered by DNA replication out of sync w/ mitosis because the cell is infected with a virus
b. Fas ligand: binds Fas protein (released by apoptotic cells)
Fas binding to Fas ligand also leads to apoptosis
TNF-receptors: TNF binds to TNF receptor on cell. If cell already stopping protein production, then apoptosis is triggered for that cell.
c. Viral Evasion of apoptosis
EX: HPV 16 and 18
*these viruses make E6, which is a protein that binds to p53
*E6-p53 comples bound by ubiquitin, which when bound to any protein, marks it for destruction
*Side note: Bcl-2 is a negative feedback mechanism for apoptosis—it turns off apoptosis
*HPV 16 and 18 make transcription factors that increase expression of Bcl-2
IV. Disabling viral nucleic acids
a. Cytosine deaminases
-enzymes that remove an NH group from cytosine converting it to uracil
-this causes a DNA mutation
-virally infected cells produce cytosine deaminases, package into capsid of retroviruses
-this produces lots of mutated C to U in new virions, hopefully destroying their ability to replicate
EX: HIV makes vif, which produces ubiquitin to attach to cytosine deaminases to degrade them
b. RNAi (RNA interference)
-in response to dsRNA, cells make enzyme, "dicer"
-cleaves dsRNA into tiny fragments
-dsRNA fragments recognized by set of other proteins, which then destroy any ssRNA homologous to dsRNA fragments
b. RNAi
