Iahi: 3.8 - Host Response And Immune Evasion

Front 1

What are the host defenses against virus infection

Back 1

- Type 1 - Interferon Response (IFN-α and IFN-β)
- Innate Immune Response (cytokines, NK, complement)
- Adaptive Immune Response (cytokines, T cells, B cells)
- Apoptotic Response

Front 2

What cells produce a lot of IFN-γ?

Back 2

Natural Killer Cells

Front 3

What is responsible for the early "anti-viral" host defense?

Back 3

Innate Immune Response:
- Cytokines: TNF-α, IL-1β, IL-6
- NK Response: IL-12 promotes NK production of IFN-γ, IL-2 promotes NK proliferation
- Complement

Front 4

What kind of adaptive immune response would you hope to elicit against a virus infection?

Back 4

Th1 response

Front 5

What kind of immunoglobulins would you hoe to make in defense against a virus infection?

Back 5

- IgA
- IgG

Front 6

What factors are released by epithelial cells infected by a virus? Function?

Back 6

IFN-α and IFN-β ---> activate NK cells (also activated by IL-12 from DCs)

Front 7

After NK cells are activated by IFN-α and IFN-β (from epithelial cells), what happens?

Back 7

Release IFN-γ, which acts on Dendritic Cells (which continue to stimulate NK cells w/ IL-12)

Front 8

What do dendritic cells do in response to a virus?

Back 8

- Present antigen to CD4+ Th0 cells
- Release IL-6 onto Th0 cells
- Release IL-12 to cause differentiation to CD4+ Th1 cells

Front 9

Once CD4+ Th1 cells have been activated, what is their role?

Back 9

Release IFN-γ onto macrophages, CD8+ Cytotoxic T cells, CD4 memory T cells, B cells (IgG)

Front 10

Which factor is important for driving the Th1 immune response?

Back 10

IFN-γ

Front 11

What is IFN-α used to treat?

Back 11

- Chronic Hepatitis C
- Melanoma
- Hair cell leukemia
- Chronic myelogenous leukemia
- Kaposi's sarcoma (HHV-8)
- Side effects: flu-like symptoms (fever, chills, headache, muscle aches, pain, malaise), problems thinking or concentrating, reduces blood counts

Front 12

What is IFN-β used to treat?

Back 12

Tx of Multiple Sclerosis (MS)
- Side effects: flu-like symptoms (fever, chills, headache, muscle aches, pain, malaise), problems thinking or concentrating, reduces blood counts

Front 13

What is IFN-γ used to treat?

Back 13

- Investigated for treatment of certain leukemias, melanomas, carcinomas
- BUT, possess properties that limit its clinical usefulness
- Side effects: flu-like symptoms (fever, chills, headache, muscle aches, pain, malaise), problems thinking or concentrating, reduces blood counts

Front 14

What kind of nucleic acids does the host recognize as foreign?

Back 14

- ssDNA
- dsRNA
- Non-methylated DNA

Front 15

What are the steps for the first host response to virus infection?

Back 15

1. Viral products (dsRNA, ssDNA, non-methylated DNA)
2. Sensed by PRRs
3. Cascade of signaling through adaptors and kinases
4. Activates transcription factors (IRFs - Interferon Response Factors - bind to ISRE - Interferon Stimulated Response Element)
5. Synthesis and secretion of IFN-α/β **Induction of Antiviral state in nearby cells**

Front 16

How does the release of IFN-α/β induce an "antiviral state" in nearby cells?

Back 16

1. Bind to receptors on nearby cells
2. JAK/STAT signaling mechanism
3. Increased synthesis of PKR (Protein Kinase R) and OAS (2'-5' Oligoadenylate Synthase)

Front 17

What leads to the activation of PKR (Protein Kinase R) and OAS (2'-5' Oligoadenylate Synthase)?

Back 17

IFN-α/β binding to receptors

Front 18

What is the role of PKR (Protein Kinase R)?

Back 18

- Binds to dsRNA (foreign) and becomes autophosphorylated (Activated)
- Then phosphorylates eIF-2α
- Phosphorylated eIF-2α can no longer deliver Met tRNA to 40S ribosome for polypeptide initiation
** Stops viral and host translation / protein synthesis **

Front 19

What is the role of OAS (2'-5' Oligoadenylate Synthase)?

Back 19

- Binds to and is activated by dsRNA
- Catalyzes synthesis of oligo adenylate from ATP, through 2'-5' linkage
- Oligo AAAA activates RNAse L (endoribonuclease)
- Binding of RNAse L to oligo AAAA induces dimerization (activation) of RNAse L, which degrades mRNA
** Stops viral and host translation / protein synthesis **

Front 20

What are the overall functions of PKR (Protein Kinase R) and OAS (2'-5' Oligoadenylate Synthase)?

Back 20

Both: shutdown protein synthesis
- PKR - translation inhibition
- OAS - mRNA degradatino (via RNAse)

Front 21

What are the outcomes of IFN-α/β inducing anti-viral state?

Back 21

- ↑ MHC Class I expression and ↑ surface class I MHC
- ↑ PKR expression
- ↑ OAS expression
- ↑ 2'-5' oligo AAAA
- ↑ Viral mRNA degradation
- ↓ Viral protein synthesis
- ↑ NK Cells

Front 22

What are the major inflammatory cytokines?

Back 22

TNF, IL-1, IL-6

Front 23

Tumor Necrosis Factor (TNF):
- Action
- Source
- Type

Back 23

- Pyrogen - can induce fever
- Produced by activated macrophages, CD4 T cells, NK cells
- Major pro-inflammatory cytokine

Front 24

IL-1β:
- Action
- Source
- Type

Back 24

- Pyrogen - can induce fever
- Produced and secreted by activated macrophages
- Major pro-inflammatory cytokine

Front 25

IL-6:
- Action
- Type

Back 25

- Activates T cells, stimulates Ab production in B cells w/ IL-1)
- Major pro-inflammatory cytokine

Front 26

What do NK cells do? What does it depend upon?

Back 26

Kill targets after assessing balance between:
- Inhibitory signals from Class I molecules
- Activating signals from NK activating ligands

Front 27

What gets up-regulated during the first response to a virus infection?

Back 27

- Type 1 IFNs (IFN-α/β) --> shuts down protein synthesis
- NK activating ligands (increases killing action of NK cells)

Front 28

In mice/humans lacking an effective NK cell response, what kind of infections thrive?

Back 28

Herpesvirus

Front 29

What can cause a cell to undergo apoptosis?

Back 29

- Factors from within (protective infected cell response)
- From without (by Fas or TNF-α on cytotoxic T cells, NK cells)

Front 30

Which signaling factor is important for apoptosis?

Back 30

Caspase (signals DNA fragmentation in nucleus)

Front 31

Which cell signals stimulate apoptosis? inhibit apoptosis?

Back 31

- p53 stimulates apoptosis
- Bcl-2, Bcl-XL inhibit apoptosis

Front 32

What viruses can encode proteins that inhibit IFN binding? Why is this beneficial?

Back 32

- Poxviruses, Herpesviruses, and Adenoviruses
- IFNs signals anti-viral state

Front 33

How do Adenoviruses evade IFN signaling?

Back 33

Encodes its own "decoy" structured RNA that binds to PKR and inhibits activation by dsRNA (prevents inhibition of protein synthesis)

Front 34

How do Poxviruses evade IFN signaling?

Back 34

- Encode dsRNA binding proteins that sequester the dsRNA and prevent PKR activation (prevents inhibition of protein synthesis)
- Also encodes an eIF2α decoy that binds to PKR and prevents it from phosphorylating eIF2α (prevents inhibition of protein synthesis)
- Also, "decoy" receptors bind to IFN and sequester it before it binds to cellular receptor

Front 35

How do Herpesviruses evade IFN signaling?

Back 35

Viral protein directs cellular phosphatase to dephosphorylate eIF-2α (prevents inhibition of protein synthesis)

Front 36

What is fever considered?

Back 36

A component of host defense that enhances inflammatory and immune response

Front 37

What viruses cause no fever to develop?

Back 37

Vaccinia virus (used to make smallpox vacccine)

Front 38

What viruses cause high fevers?

Back 38

Poxvirus recombinants lacking IL-1β binding protein

Front 39

How do viruses evade the complement system?

Back 39

- Viruses (poxvirus, CMV, KSHV, HIV) encode homologs of complement control proteins
- Prevents the assembly of the MAC complex
- Can encapsidate viral or host complement control proteins in membranes to evade complement-mediated lysis

Front 40

How do viruses affect the surface expression of Class I MHC molecules?

Back 40

- Degrade TAP transporter (herpesvirus)
- Block peptide transport into ER by blocking TAP transporter (CMV, HSV)
- Degrade Class I MHC molecules (CMV)
- Retain Class I MHC molecules in ER / Golgi (adenovirus, CMV)
- Divert Class I MHC to lysosomes for degradation (HHV-6,7, HIV)
- Down-regulate transcription of components of MHC molecule (adenovirus)

Front 41

How do viruses evade NK cell killing?

Back 41

- Modulate removal of MHC-1 from surface of infected cells (removing some HLA-A and -B, but leaving HLA-C on surface)
- Encode "decoy" MHC-1-like molecules to interact w/ inhibitory NK receptors
- Prevent activating NK cell receptor ligands from arriving at cell surface by retaining them in ER or rerouting to lysosomes

Front 42

What other molecules in immunological synapse than TCR and Class I MHC molecule can viruses regulate for immune evasion?

Back 42

- Adhesion molecules (ICAM-1)
- Costimulatory molecules (CD80/CD86 (B7))

Front 43

What are ways viruses can inhibit apoptosis?

Back 43

- Soluble, secreted vTNF-Receptors
- Viral proteins that remove Fas from cell surface
- v-caspase inhibitors
- Viral homologs of Bcl-2
- p53 inhibitors

Front 44

Which kind of viruses use epitope mutation to evade the immune system? Why?

Back 44

Viruses with small genomes (because they replicate much faster than hosts)

Front 45

Why must the set point of the immune system be finely tuned?

Back 45

- Too little host defense - virus takes over
- Too much inflammatory response - severe disease