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Flashcards in Host Defenses Deck (29):
1

Innate Immune Response

Cytokine Response

NK Response

Complement

2

Adaptive Immune Response

Cytokine Response

T Cell Response

B cell Response (antibodies)

3

Innate Immunity after virus infection

  1. Recognition of patterns by PRRs
  2. Type I IFN secretion
  3. Secretion of other solule mediators: 
    1. Cytokines - IL-1, TNFα, IFNγ, chemokines etc
  4. Complement
  5. NK cells
    1. Direct killing of virus infected cells
    2. Huge source of IFNγ production

4

Adaptive Immunity after virus infection

  1. Cytokines
  2. Cytotoxic T cells
    1. Granule exocytosis
    2. Fas L induced apoptosis
  3. B-cells and antibodies
    1. Neutralization
    2. Opsonization
    3. Phagocytosis

5

NK acitivity is 20-100x better when _____ and/or _____ or present

IFNs; IL-12

6

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

7

Inteferon ß used in treatment of ________ ________

Multiple Sclerosis

8

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

9

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)

10

Signaling pathway used by Type I inteferons

Jak/STAT pathway

11

Type I IFNs activate ___ and ____ __________ ______

PKR; 2'-5' Oligoadenylate Synthase

12

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

 

13

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

14

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

15

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

16

NK cells kill targets after assessing the balance between...

  • Inhibitory signals from class I molecules
  • Activating signals from NK activating ligands

17

Infected cells are often induced to undergo _______

apoptosis

18

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)

19

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

20

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)

21

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

22

Fever

Considered a component of host defense that enhances inflammatory and immune response - fever inducing candidates = IL-1/IL-6/TNF-α

23

Poxvirus recominants lacking the _____ _____ _____ have been generated - when mice are infected with these viruses...they develop fevers

IL-1ß binding protein

24

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

25

How do viruses avoid complement MAC complex

Can encode homologs of complement control proteins that prevent assembly of MAC complex

Can encapsidate viral or host complement control proteins in their membranes to evade complement-mediated lysis

26

How do viruses avoid T-cell response (6)

Viruses strategize to affect the surface expression of MHC and NK ligands

  1. Degrade TAP transporter
  2. Block peptide transport into ER by blocking TAP transporter
  3. Degrade class I MHC molecules
  4. Retain class I MHC molecules in ER/Golgi
  5. Divert class I MHC to lysosomes, where it is degraded
  6. Downregulate transcription of components of the MHC molecule

27

To evade NK cell killing, viruses can:

  • Modulate the removal of MHC-I from the surface of infected cells, removing some HLA-A and -B but leaving HLA-C on the surface
  • Encode decoy MHC-I-like molecules that interact with inhibitory NK receptors
  • Prevent activating NK cell receptor ligands from arriving at the cell surface by retaining them in the ER, or rerouting them to lysosomes

28

Viruses induce the downregulation of other molecules in the immunological synapse:

  • Adhesion molecules (ICAM-I)
  • Costimulatory Molecules (CD80/CD86/B7)

29

Viral mechanisms to prevent apoptosis

  1. Virus-encoded soluble TNF receptors
  2. VIral inhibitors of capsases that block various proteolytic steps of capsase activation and target protein cleavage
  3. Virus-encoded homologs of "anti-apoptotic" proteins such as Bcl-2
  4. Virus-encoded inhibitors of p53, a major inducer of "apoptosis from within"