Lecture 5- antiviral innate immunity

Question 1

briefly describe antiviral innate immune response

Answer 1

• type 1 interferons
• includes interferons B and several interferon a’s
• produced in response to viral (and some pathogens) infections
• acts in both autocrine and paracrine to protect from further viral infection

Question 2

describe viral detection and response

Answer 2

viruses fuse through the membrane, its nucleic acids enter (TLR 7/8 and 3 recognize RNA ; TLR 9 recognizes DNA), these TLR’s activate transcription factors- IRF-1, IRF-7 and IRF-3, which move to nucleus and initiate transcription of IFN-a and IFN-B

Question 3

IFN-B works in a (autocrine/paracrine) fashion
IFN-a…

Answer 3

IFN-B pracrine
IFN-a autocrine

Question 4

both INF-alpha and INF-beta bind to ___ receptor

Answer 4

type 1 interferon receptor

Question 5

all the IRF’s are ___, they move to nucleus and initiate IFN’s

Answer 5

transcription factors

Question 6

Which are the PRR that recognize viral nucleic acids in the cytosol?

Answer 6

RIG-I, MDA5

Question 7

what is the “anti-viral” state

Answer 7

Created in neighboring cells, protects the virus from invading the cells

• IFN receptor goes to uninfected cell– inhibition of viral protein synthesis, degradation of viral RNA, inhibition of viral gene expression and virion assembly

Question 8

how do RIG-I-like receptors play a major role in type 1 IFN induction upon viral infection?

Answer 8

RIG-I facilitates activation of 2 types of responses:
1. activates IRF3- causes synthesis and secretion of type 1 interferons (IFN-a and B)
2. activates NFkB- causes synthesis and secretion of inflammatory cytokines

Question 9

TLR7 in endosome binds RNA and signals via ___ to induce IFN gene expression of ___

Answer 9

MyD88
IFN-a & IFN-B

Question 10

TLR4 in endosome binds RNA and signals via ___ to induce IFN gene expression of ___

Answer 10

TRIF
IFN-B

Question 11

name 2 TLR’s that induce strong type 1 interferon responses

Answer 11

TLR7 and TLR3

Question 12

What effects does type I interferon have on NK cells? Type 1 works with NK cells

Answer 12

NK cells
1. are activated by type 1 interferon- type 1 IFN drives the differentiation of NK cells into cytotoxic effector cells
2. type 1 IFN is a signal for NK cells to proliferate- make more NK cells

Question 13

describe NK cells

Answer 13

• lymphocytes of the innate immune system
• potent killers of infected or “aberrant” cells
• killing activity is balanced by activating and inhibitory receptors- recognize either altered or normal ligands on target cells

Question 14

name 2 functions of NK cells

Answer 14

1- killing of infected/damaged cells
2-production of cytokines to activate macrophages

Question 15

describe the 2 receptors of NK cells

Answer 15

• health cells bind inhibitory receptor, sends a negative signal to prevent killing
• infected cell still has inhibitory receptor with negative signal but also activating receptor which sends a stronger signal- killing the cell (outcome may be different based on strengths of signals)

Question 16

describe KIR’s

Answer 16

NK cell receptors are designated KIR’s: killer cell immunoglobulin-like receptor
- KIR’s can be either activating or inhibitory receptors

• activating bind infected/pathogenic proteins and have short cytoplasmic tails which interact with adaptor molecules
• inhibitory bind to normal MHC class I and have long cytoplasmic tails

Question 17

What type of NK cell function would you predict in a patient deficient in the KIR signaling adapter, DAP12?

Answer 17

DAP12 is with activating receptors, so without it, cannot kill cell

Question 18

describe NK cells mechanism of killing

Answer 18

formation of NK killing “synapse” through tight association of target cell with NK cell

-When NK cells recognize activation with little inhibition, focus themselves on target cell and deliver a lethal hit- degranulate on surface, form pores and deliver molecules that will activate an apoptotic cascade
- these molecules are
1. perforin: pore forming molecule, much in common with C9 of complement cascade
2. granzymes: are delivered through the pore, activate apoptotic cascade and caspases
- cause DNA cleavage, nuclear fragmentation, membrane blebbing- apoptosis

Question 19

what is clinical significance of killer cell function?

Answer 19

many killing mechanisms are shared between NK and cytolytic T cells
- perforin and granzymes

differences in their responses due to specificity of their receptors
- NK cells kill target cells that express a combo of too little MHC and too many activating ligands
- T cells kill target cells that present the specific MHC-peptide complex for which they are specific

Question 20

describe function 2 of NK cells, production of cytokines to activate macrophages

Answer 20

produce IFN-gamma to stimulate activation of macrophages and increase their killing ability

Question 21

name 3 cytokines of the innate response

Answer 21

1. Interleukin-1 (IL-1)
2. TNF-a
3. IL-6

they all stimulate innate response in liver, activate inflammation and fever