17 - Viral Evasion of Innate Immunity Flashcards
Viral infection immunity
- Prevented by type 1 interferons (innate) and neutralising antibodies (adaptive)
- Infected cells are eliminated by NK cells (innate) and CTLs (adaptive)
Order of innate and adaptive responses
Type 1 IFNs –> NK cells –> CTLs –> Antibodies
TLRs
- Are pattern recognition receptors (PRRs) that are ligated by pathogen associated molecular patterns (PAMPs)
- PAMP ligation of TLR induces signal cascade that results in synthesis of pro-inflammatory cytokine and typer 1 IFNs
Example of TLRs
TLR3- and RIG-1 recognising dsRNA
TLR-3 and RIG-1
- PAMP (dsRNA) is recognised by PRR: transmembrane protein TLR-3 or RIG-1 (in the cytoplasm)
- PRR undergoes conformational change and induced signal transduction cascade causing cytokine secretion
Binding of dsRNA to TLR3
Induces dimerisation and activation of downstream signalling
Hepatitis C virus (HCV)
- ssRNA virus of the Flaviviridae family
- Persistent HCV infections are associated with progressive liver fibrosis and hepatocellular carcinoma
- HCV is sensed by TLR3 through detection of dsRNA intermediates in infected hepatoma cells
- ACtivated TLR3 signalling cascade leads to synthesis of type 1 and 2 IFNs, expression of ISGs and pro inflammatory cytokines that limit HCV replication
Why does treatment with IFNs eliminiate HCV in only 50% of patients
As viral proteins can interfere with TLR mediated pathways through different mechanism
HCV NS3/4A
HCV exploits its NS3/4A protease to cleave TRIF (adapter responding to
TLR activation and mediates type I IFN production)
HTLV-1 protein 30 or HBV HBeAg
Directly reduce the expression of TLRs by interacting with their transcriptional factors
HBV HBsAg
Inhibits the expression and nuclear localisation of IRF7
Cytokine secretion inducing an antiviral state
- RIG-1 detects the presence of viral dsRNA in a cell
- The cell responds by secreting IFNα/β
- IFNα/β binds to its receptor on nearby cells, inducing an antiviral state and thus preventing virion offspring replication
The antiviral state
Genes induced by interferon are called interferon stimulated genes (ISGs)
Examples of ISGs
- Tetherin interferes with viral budding (enveloped viruses)
- Mx1 prevents nucleocapsid trafficking
- PKR, OAS and RNase L block translation of mRNA synthesis
Type 1 IFN signal transduction cascade
- IFNα/β binds to its receptor, JAK1 and TYK2 are activated and form a complex with STAT1 and STAT2
- JAK and TYK2 then phosphorylate STAT1 and STAT2, which subsequently dimerize
- The phosphorylated heterodimer forms a complex with the IRF9 transcription factor
- The complex enters the nucleus where it activates ISG transcription
Viral evasion of type 1 IFN
- Poxvirus protein binds to type 1 IFN before the IFNα/β can bind to its cellular receptor
- SARS and HepC induce ubiquitination and subsequent proteolysis of IFN receptor
- Several viruses target STAT1 to the proteasome
- Some virally encoded proteases degrade STAT2
- Other viruses prevent JAK1 or TYK2 from phosphorylating the STATs
- Viral phosphatase can dephosphorylate STAT1, blocking dimerisation with STAT2
- Some viruses block transcription of ISGs by interfering with IRF9 activity
Example of viruses evading the specific proteins expressed by ISGs
PKR is targeted by many viruses, using different mechanisms
PKR is targeted by many viruses, using different mechanisms
- Vaccinia virus and reoviruses encode proteins that bind to dsRNA, sequestering it away from activating PKR
- HepC, HSV-1 encode proteins that directly bind PKR preventing it from blocking translation
- CMV interferes with the normal cytoplasmic localisation of PKR, causing it
to accumulate in the nucleus where it can’t block translation
Neutrophils
Produce neutrophil extracellular traps (NETs) in the presence of viral infection
How do NETs help control viral infection
- Trapping virions, immobilising them
- Contain antiviral components than can inactivate viruses
- Stimulate other immune cells
Viral evasion of NET
- Cytokine IL-10 suppresses NET formation (viruses stimulate infected cells to produce IL-10 and some encode IL-10 homologs)
- Some viruses produce their own DNAses that degrade DNA component of NET
MHC Class 1
- ‘Sample’ the cell cytoplasm contents and present them for inspection by other immune cells
- In uninfected cells, peptides presented are self antigens
- In infected cells, peptides presented are viral, triggering antiviral responses
Viral evasion of MHC-1
- Produce abundant viral protein that is resistant to degradation by the proteasome and thus reduces viral epitope display e.g. EBV
- Several herpesviruses encode proteins that block the function of TAP, preventing transport of peptides from the proteasome into the ER
- Target vesicles containing MHC-I epitope complexes to the lysosome so that the complexes get degraded
- Viruses can also encode proteins that block MHC-I epitope complexes from leaving the Golgi apparatus
How do NK cells kill infected cells
- Perforin creates channels in the cell membrane, which permits the entry of granzyme proteins ultimately triggering apoptosis of the infected cell.
- Inhibited by self antigens presented by MHC-1
Evasion of NK cells
- Encoding viral MHC-1 homologs which mimic host MHC-1 and can engage the NK inhibitory receptor
- Produce anti-apoptotic proteins to prevent cell deatg
Three ways complement system counteracts infection
- MAC
- Opsonisation of extracellular virions
- Chemoattraction
Evading complement
- Dengue NS1 targets C4
- Smallpox SPICE (smallpox inhibitor of complement enzymes)
- Influenza M1 interacts with C1qA (part of C1 complex)
What are innate immune reactions triggered by
Pathogen-associated molecular patterns (PAMPs) - e.g. dsRNA
Innate immunity
React to groups of microbes (are not specific), and react the same every time they are triggered
