Host Defenses

Question 1

Innate Immune Response

Answer 1

Cytokine Response

NK Response

Complement

Question 2

Adaptive Immune Response

Answer 2

Cytokine Response

T Cell Response

B cell Response (antibodies)

Question 3

Innate Immunity after virus infection

Answer 3

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

Question 4

Adaptive Immunity after virus infection

Answer 4

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

Question 5

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

Answer 5

IFNs; IL-12

Question 6

Interferon α use in virus infections

Answer 6

• Used in the treatment of chronic Hepatitis C
• Also used in the treatment of melanoma, hairy cell leukemia, chronic myelogenous leukemia, Kaposi’s sacroma

Question 7

Inteferon ß used in treatment of ________ ________

Answer 7

Multiple Sclerosis

Question 8

Why don’t we generally use Interferon γ

Answer 8

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

Question 9

The first response to virus infection: Type I Interferons (IFN- α/ß)

Answer 9

• 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)

Question 10

Signaling pathway used by Type I inteferons

Answer 10

Jak/STAT pathway

Question 11

Type I IFNs activate ___ and ____ __________ ______

Answer 11

PKR; 2’-5’ Oligoadenylate Synthase

Question 12

PKR (Protein Kinase R)

Answer 12

• 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

Question 13

OAS (2’-5’ Oligoadenylate Synthetase is also induced by IFN)

Answer 13

• 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

Question 14

IFN-α/ß induce the Anti-Viral State which consists of:

Answer 14

Increased:

• MHC class I expression
• PKR expression
• 2’-5’ snthase expression
• 2’-5’ oligo A (A-A)
• Viral mRNA degradation

Question 15

Pro Inflammatory Cytokines

Answer 15

• 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

Question 16

NK cells kill targets after assessing the balance between…

Answer 16

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

Question 17

Infected cells are often induced to undergo _______

Answer 17

apoptosis

Question 18

Two types of “programmed cell death”

Answer 18

• From within (a protective “selfless” infected cell response)
• From without (Fas or by TNF-α on cytotoxic T cells, NK cells)

Question 19

Cellular mechanisms of Apoptosis

Answer 19

• 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

Question 20

How do viruses prevent IFN signaling extracellularly

Answer 20

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)

Question 21

How do viruses prevent IFN signaling from within:

Answer 21

• 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

Question 22

Fever

Answer 22

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

Question 23

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

Answer 23

IL-1ß binding protein

Question 24

What prevents complements from destroying normal cells

Answer 24

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

Question 25

How do viruses avoid complement MAC complex

Answer 25

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

Question 26

How do viruses avoid T-cell response (6)

Answer 26

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

Question 27

To evade NK cell killing, viruses can:

Answer 27

* 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

Question 28

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

Answer 28

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

Question 29

Viral mechanisms to prevent apoptosis

Answer 29

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"