17 - Viral Evasion of Innate Immunity

Question 1

Viral infection immunity

Answer 1

• Prevented by type 1 interferons (innate) and neutralising antibodies (adaptive)
• Infected cells are eliminated by NK cells (innate) and CTLs (adaptive)

Question 2

Order of innate and adaptive responses

Answer 2

Type 1 IFNs –> NK cells –> CTLs –> Antibodies

Question 3

TLRs

Answer 3

• 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

Question 4

Example of TLRs

Answer 4

TLR3- and RIG-1 recognising dsRNA

Question 5

TLR-3 and RIG-1

Answer 5

• 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

Question 6

Binding of dsRNA to TLR3

Answer 6

Induces dimerisation and activation of downstream signalling

Question 7

Hepatitis C virus (HCV)

Answer 7

• 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

Question 8

Why does treatment with IFNs eliminiate HCV in only 50% of patients

Answer 8

As viral proteins can interfere with TLR mediated pathways through different mechanism

Question 9

HCV NS3/4A

Answer 9

HCV exploits its NS3/4A protease to cleave TRIF (adapter responding to
TLR activation and mediates type I IFN production)

Question 10

HTLV-1 protein 30 or HBV HBeAg

Answer 10

Directly reduce the expression of TLRs by interacting with their transcriptional factors

Question 11

HBV HBsAg

Answer 11

Inhibits the expression and nuclear localisation of IRF7

Question 12

Cytokine secretion inducing an antiviral state

Answer 12

• 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

Question 13

The antiviral state

Answer 13

Genes induced by interferon are called interferon stimulated genes (ISGs)

Question 14

Examples of ISGs

Answer 14

• Tetherin interferes with viral budding (enveloped viruses)
• Mx1 prevents nucleocapsid trafficking
• PKR, OAS and RNase L block translation of mRNA synthesis

Question 15

Type 1 IFN signal transduction cascade

Answer 15

• 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

Question 16

Viral evasion of type 1 IFN

Answer 16

• 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

Question 17

Example of viruses evading the specific proteins expressed by ISGs

Answer 17

PKR is targeted by many viruses, using different mechanisms

Question 18

PKR is targeted by many viruses, using different mechanisms

Answer 18

• 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

Question 19

Neutrophils

Answer 19

Produce neutrophil extracellular traps (NETs) in the presence of viral infection

Question 20

How do NETs help control viral infection

Answer 20

• Trapping virions, immobilising them
• Contain antiviral components than can inactivate viruses
• Stimulate other immune cells

Question 21

Viral evasion of NET

Answer 21

• 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

Question 22

MHC Class 1

Answer 22

• ‘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

Question 23

Viral evasion of MHC-1

Answer 23

• 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

Question 24

How do NK cells kill infected cells

Answer 24

• 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

Question 25

Evasion of NK cells

Answer 25

• 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

Question 26

Three ways complement system counteracts infection

Answer 26

• MAC
• Opsonisation of extracellular virions
• Chemoattraction

Question 27

Evading complement

Answer 27

• Dengue NS1 targets C4
• Smallpox SPICE (smallpox inhibitor of complement enzymes)
• Influenza M1 interacts with C1qA (part of C1 complex)

Question 28

What are innate immune reactions triggered by

Answer 28

Pathogen-associated molecular patterns (PAMPs) - e.g. dsRNA

Question 29

Innate immunity

Answer 29

React to groups of microbes (are not specific), and react the same every time they are triggered