Host Defenses Flashcards
Innate Immune Response
Cytokine Response
NK Response
Complement
Adaptive Immune Response
Cytokine Response
T Cell Response
B cell Response (antibodies)
Innate Immunity after virus infection
- Recognition of patterns by PRRs
- Type I IFN secretion
- Secretion of other solule mediators:
- Cytokines - IL-1, TNFα, IFNγ, chemokines etc
- Complement
- NK cells
- Direct killing of virus infected cells
- Huge source of IFNγ production
Adaptive Immunity after virus infection
- Cytokines
- Cytotoxic T cells
- Granule exocytosis
- Fas L induced apoptosis
- B-cells and antibodies
- Neutralization
- Opsonization
- Phagocytosis
NK acitivity is 20-100x better when _____ and/or _____ or present
IFNs; IL-12
Interferon α use in virus infections
- Used in the treatment of chronic Hepatitis C
- Also used in the treatment of melanoma, hairy cell leukemia, chronic myelogenous leukemia, Kaposi’s sacroma
Inteferon ß used in treatment of ________ ________
Multiple Sclerosis
Why don’t we generally use Interferon γ
Side Effects:
- Flu like symptoms following each injection
- Problems with thinking and concentration
- Reduce blood counts
- These symptoms occur in up to half of all patients
The first response to virus infection: Type I Interferons (IFN- α/ß)
- Viral products (dsRNA, ssDNA, unmethylated DNS)
- Sensed by PRRs (TLRs)
- Cascade of signaling through adaptors, kinases
- Activates Transcription factors (IRFs - Interferon response factors bind to ISRE - Inteferon Stimulated Response Element)
- Synthesis and secretion of IFN- α/ß (Induction of ANTIVIRAL STATE in nearby cells)
Signaling pathway used by Type I inteferons
Jak/STAT pathway
Type I IFNs activate ___ and ____ __________ ______
PKR; 2’-5’ Oligoadenylate Synthase
PKR (Protein Kinase R)
- Binds to dsRNA and becomes autophosphorylated - it is a PRR
- It then phosphorylates eIF-2α
- eIF-2α delivers Met tRNA to the 40s ribosome to initiate polypeptide synthesis
- When eIF-2 α is phosphorylated, translation is prevented
OAS (2’-5’ Oligoadenylate Synthetase is also induced by IFN)
- Binds to and is activated by dsRNA
- Catalyzes synthesis of oligo adenylate from ATP, through a 2’-5’ linkage
- Oligo AAAA activates RNAse L - an endoribonuclease
- Binding of RNAseL to oligo AAA induces dimeration (activation) of RNAse L, which degrades mRNA
End Result: mRNA degradation - shutdown of protein synthesis
IFN-α/ß induce the Anti-Viral State which consists of:
Increased:
- MHC class I expression
- PKR expression
- 2’-5’ snthase expression
- 2’-5’ oligo A (A-A)
- Viral mRNA degradation
Pro Inflammatory Cytokines
- TNF
- A pyrogen - can induce fever
- Produced by activated macrophages, CD4 T cells, and NK cells
- IL-1ß
- A pyrogen
- Major pro-inflammatory cytokine
- Produced and secreted by activated macrophages
- IL-6
- Major pro-inflammtory cytokine
NK cells kill targets after assessing the balance between…
- Inhibitory signals from class I molecules
- Activating signals from NK activating ligands
Infected cells are often induced to undergo _______
apoptosis
Two types of “programmed cell death”
- From within (a protective “selfless” infected cell response)
- From without (Fas or by TNF-α on cytotoxic T cells, NK cells)
Cellular mechanisms of Apoptosis
- Cytochrome C released from mitochondria by p53 interaction with Bax/Bak pores
- Cytochrome C induces production of capsase-9 which becomes capsase-3
- Causes cell death
- TNF-R can also induce production of capsase-3
How do viruses prevent IFN signaling extracellularly
Viruses encode proteins to prevent IFN binding to receptors
This protein binds to type 1 interferons preventing them from binding the actual receptors (same for IFN-γ)
How do viruses prevent IFN signaling from within:
- Viruses can encode their own structured RNA to bind to PKR and inhibits activation by dsRNA
- Herpesvirus encode a protein that recruits a cellular phosphatase that cleaves the phosphate from eIf-2α
- Poxviruses encode dsRNA binding proteins that sequester the dsRNA and prevent PKR activation
- Poxviruses also encode eIF2α decoy that binds to PKR and prevents it from phosphorylating eIF2α
Fever
Considered a component of host defense that enhances inflammatory and immune response - fever inducing candidates = IL-1/IL-6/TNF-α
Poxvirus recominants lacking the _____ _____ _____ have been generated - when mice are infected with these viruses…they develop fevers
IL-1ß binding protein
What prevents complements from destroying normal cells
Cells encode “Control” proteins on their surface that block complement activation. Bacterial surfaces lack these complement control proteins so complement can activate antibody-independent virolysis
