512 Exam 2 Lecture 17

What are intrinsic resistance factors?

proteins or RNAs that are present in an uninfected host that can limit or block virus replication upon detection

What is apoptosis and how might it restrict virus replication?

programmed cell death

destroy infected cell without initiating inflammatory response

How does apoptosis limit inflammation from a dying cell?

specific signals trigger the activation of caspases that carry out the death pathway

caspases: cleave targets

contents remain within membranes which prevents inflammation

What is autophagy and how does it restrict virus replication? How do viruses subvert autophagy for their own benefit?

mechanism for recycling of redundant or damaged cell content (i.e. mitochondria)

restricts may inhibiting replication at multiple steps of the viral lifecycle

for their own benefit by utilizing double-membrane vesicles as a platform for replication

What type of species use RNAi for antiviral defense?

eukaryotes

Describe how RNAi works? What are the major cellular factors required for RNAi?

• dsRNA produced during infection cleaved by DICER into small RNAs - termed small-interfering RNAs

• siRNAs are loaded into RISC (RNA Induced Silencing Complex)

• RISC identifies viral mRNAs containing identical sequences

• Slicer, a nuclease in RISC, cleaves viral RNA

What is CRISPR and how does it contribute to immunological memory?

CRISPR: clustered regularly interspaced short palindromic repeat (defense mechanism)

Contributes to immunological memory as the phage genome fragments are incorporated into the genome, this memory is transferred to subsequent generations

What is a PAMP and what are some common PAMPs that illicit an innate immune response?

PAMP: pathogen-associated molecular pattern

• detects the pathogen; must identify specific aspects

Common PAMPS:

• dsRNA or ssRNA in endosomes

• DNA in the cytoplasm or unique nuclear compartments

• specific viral proteins

What is a PRR?

Pattern-recognition receptor

* cytosolic RNA sensors that continuously survey the cytoplasm for dsRNA

Which PRRs are membrane bound? Where do they detect PAMPs?

Toll-like receptors are membrane bound

detect PAMPs on cell surface or in endosomes

Which PRRs detect RNA/DNA in the cytoplasm?

RIG-I

RLRs

DNA sensors

Describe innate immune signaling starting with a PRR

• interaction of PRRs with viral nucleic acids leads to activation of signaling cascades

• cascades require unique signaling platform proteins

• result in activation of transcription factors that go to the nucleus and initiate transcription of IFN genes

What transcription factors drive this response?

NFkB and IRF-3

What is IFN? How does it stimulate the production of ISGs? What transcription factors does it activate?

IFN: interferon; interfered with virus replication

• IFN secreted from the cell

• bind to receptor which initiates another signaling cascade involving JAK-STAT signaling

• STAT proteins are phosphorylated which induced their translocation to the nucleus

• STAT proteins act as transcription factors to initiate transcription of genes

• final result: production of IFN stimulated genes or ISGs

Be able to describe each of the ISGs discussed in the slides.

1. APOBEC3G: cytodine deaminase (mutates viral DNA)

2. Zinc-antiviral protein (ZAP): binds viral RNA at CG dinucleotides and recruits cellular enymes to degrade it

3. Tetherin: binds to viral particles and prevents their release

4. IFITM3 (IFN transmembrane 3): blocks entry of enveloped viruses

5. Ly6E: prevents membrane fusion of enveloped viruses

6. TRIM5alpha: inhibits HIV uncoating

Match the term to the following category:

apoptosis

caspase

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autophagy

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RNAi

• Dicer

• RISC

• siRNA

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CRISPR

* Cas proteins

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Pattern-associated molecular pattern (PAMP)

• dsRNA

• cytoplasmic DNA

• ssRNA

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PRR (RNA/DNA sensor)

• Mda-5

• RIG-1

• cGAS

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Signaling platform protein

• myD88

• MAVs

• STING

Match the term to the following category:

Interferon-stimulated gene (ISG)

• ZAP

• Tetherin

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Signal transducing transcription factors

• STATS

• NFkB

• IRF-3