Lec 17 - Innate immune responses to viral infection Flashcards
Compare innate and adaptive according to the following:
- Cells that kill
- Mechanism of immunity
- How mechanism is achieved
- Cells = innate has NK cells vs adaptive has CD8+ T cells
- Mechanism = innate uses antiviral state vs adaptive uses neutralisation
- How = innate uses IFNs vs adaptive uses antibodies
List the stages of the kinetics of the combined innate and immune response to viruses.
- Type 1 IFNs peak at day 2-3
- NK cells peak at day 3-4
- Virus titre peaks at day 5 and adaptive response begins
- Virus specific CD8+ T cells peak at day 7-8, plateau, decline after day 11
- Antibodies peak at day 10-12 then decline
What are TLRs, where are they located, and what do they result in?
- Type of PRRs ligated by PAMPs
- Transmembrane or cytosolic
- Signal cascade to pro-inflammatory cytokines and type 1 IFNs = TNF-a, IFN-y and IL1, 6, 8, 12
How do TLR-3 and RIG-1 recognise dsRNA? Where are each located?
- TLR-3 = transmembrane in endosome
- RIG-1 = cytoplasm
1. dsRNA PAMP binds either receptor
2. Conformational change to get signal transduction
3. Cytokines and type 1 IFNs produced from IFN stimulated genes
4. Cells less/non permisive to infection
Describe TLR-3’s structure. How does TLR-3’s conformation change after being ligated?
- Leucine rich repeat (LRR) domain = external part
- Transmembrane (TM) domain
- Toll interleukin receptor 1 resistance (TIR) domain = associates 2 receptors together for signal transduction
- LRR ligated then dimerisation from 2 receptors associating by TIR
How does HCV and HBV interfere with TLR pathways?
HCV = viral protease cleaves TRIF to stop signal transduction
HBV = HTLV-1/HBeAg interacts with TFs to reduce TLR expression
= HBsAg inhibits expression and transport of IRF7 for IFN regulation
What are the 4 different ways genes induced by IFN stimulated genes (ISGs) trigger the antiviral state?
- Tetherin prevents budding
- Mx1 prevents nucleocapsid movement
- PKR, OAS and RNase L block translation
- Procaspase B triggers apoptosis hypersensitivity
Describe the steps in type 1 IFN signal transduction cascade process.
- IFN-alpha/beta binds receptor and activates JAK1 and TYK2
- JAK1 and TYK2 form complex with and phosphorylate STAT1 and 2 to make heterodimer
- Heterodimer complexes with IRF9 TF
- Complex enters nucleus and activates ISG transcription
What are the 7 ways viruses evade type 1 IFNs? Give examples of viruses for each method.
- Bind IFN before it binds receptor eg poxvirus
- Induce ubiquitination of IFN receptor eg SARS, HCV
- Viral proteins bind PKR to prevent blocking of viral translation eg HCV, HSV-1
- Prevent JAK1/TYK2 from phosphorylating STATs eg Marburg
- Interfere with IFR9 to block ISG transcription eg HPV
- Viral proteins bind dsRNA to prevent it activating PKR eg vaccinia, reovirus
- Interfere with cytoplasmic localisation of PKR so it accumulates in nucleus eg CMV
How do neutrophils contribute to viral immunity?
Neutrophil extracellular traps (NETs)
- Trap virions
- Antivirals to inactivate
- Stimulate immune cells
How do viruses evade NETs?
- Stimulate IL-10 production or have homologs to suppress NET formation
- Encode DNAses to degrade NETs
How do viruses evade MHC-1 presentation? Describe how Epstein Barr virus and Herpesvirus specifically evade presentation.
- Target MHC-1 vesicles for lysosomal degradation
- Viral proteins block MHC-1-epitope complexes leaving Golgi body
- Epstein Barr virus = viral proteins are resistant to degradation = less epitopes displayed
- Herpesvirus = viral proteins block TAP to prevent transport of viral peptides to ER
NK cells are activated by reduced MHC-1 failing to bind inhibitory receptors. How do viruses evade this?
- Encode MHC-1 homologs to bind inhibitory receptor
- Produce anti-apoptotic proteins
How do dengue, smallpox and influenza evade the complement system?
- Dengue = NS1 targets C4 to prevent conversion to C3 and C5 in the classical pathway
- Smallpox = SPICE targets C3b and C4b to block classical and alternative pathways
- Influenza = M1 interacts with C1qA in C1 complex to block classical pathway
