Viral Immune Modulation Flashcards by Claire Delargy

Host survival following infection requires …

Efficient innate immunity
Efficient adaptive immunity

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Virus replication requires …

Modulation of innate immunity and/or
Modulation of adaptive immunity

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Balance between host anti-viral responses and virus immune modulation is…

Essential for survival of both

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Modulation of innate immune system is…

Intracellular
Extracellular

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What modulates antigen presentation?

DC/T cell interactions

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Modulation of lymphocyte clonal expansion

Lymphoproliferation block

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“Classical” IFN induction pathway - 1st Wave

Virus attaches to cell -> Introduces PAMPS into cell e.g. dsRNA -> recognised by PRRs eg RIG-I or PKR in the cytosol -> Activates signalling cascade eg IFR-3 or NFkB -> TFs form complexes which migrate to nucleus -> induces transcription of IFN-beta -> IFN-beta released from cell

Alternatively dsRNA can be recognised by TLR3 on the cell surface.

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“Classical” IFN induction pathway - 2nd wave

IFN-beta released from infected cell -> IFNAR present on surface of neighbouring cells -> triggers activation of JAKSTAT pathway (phosphorylated JAK phosphorylate STAT, dimerise) -> forms complex with IRF9 to create ISGF3 -> translocate to nucleus -> binds to ISRE present on ISGs to activate them -> produce proteins with antiviral activity eg ISG20, Mx proteins, OAS proteins
Cytokines and chemokines released amplify the response - immune and interferon

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IRF-7

Interferon response factor 7
Constitutively expressed in pDCs Master regulator of IFN-α gene expression

pDCs= Plasmacytoid dendritic cells

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Inhibition of dsRNA signalling

MDA-5 or RIG-I blocked in cytoplasm eg V proteins of SV5, SeV, hPIV2, MeV, HeV

IRF-3 responsive promoters blocked eg NiV V

IRF-3 blocked in nucleus eg NiV W

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Inhibition of IFN signalling - Rubulavirus V proteins (C-ter)

STATS to proteasome by ubiquitination

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Inhibition of IFN signalling - Respirovirus C proteins (C-ter)

Inhibit STAT1, STAT2 or TYK2 tyrosine phosphorylation

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Inhibition of IFN signalling - Morbillivirus V proteins (C-ter)

Inhibit STAT1, STAT2 tyrosine phosphorylation
STAT1/IFNr complex retained

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Inhibition of IFN signalling - Henipavirus P, V, W (N-ter)

STATs sequestered in high molecular weight complexes

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Inhibition of IFN signalling - Pneumovirus NS1 and NS2

STAT2 to proteasome

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Virus IFN targets

->IFN induction pathway - RIG-I
-> basic transcription - IFN a/b
-> IFN signalling pathway - STAT 1/2
-> IFN effectors - PKR, OAS, Mx

Role of Type I IFN system (IFN α/β)

Major player in antiviral defence
Secreted in response to viral infection
Induce expression of potent antiviral mechanisms

Virus ability to block type I IFN system
determines …

Virulence
Interspecies transmission

Modulation of extracellular innate immune system is mainly achieved by

Release of viral chemokine modulatory proteins

Chemokine network regulates(4):

Leukocyte locomotion
T cell differentiation
Angiogenesis
Mast cell degranulation

Tight control vital for proper immune function
Virus encoded genes modulate chemokine network

Chemokines and their classes

~47 known chemokines, 19 known chemokine receptors. 8-10 kDa

4 classes of chemokines, based on location of 2 cys residues
CXC (alpha) – soluble
CC (beta) – soluble
C (gamma) – soluble
CX3C (delta) – membrane-bound

Virus immune stealth and virus immune activation by chemokines

Immune stealth
Blocking/modulation of chemokine function
Prevents clearance of virus-infected cells

Immune activation
Expression of virus-encoded chemokines or chemokine receptors
Provides a window for virus dissemination

Virus interference in the regulation of the chemokine network

Virus-encoded cytokines
Modulate host chemokine responses

Virus-encoded chemokines, receptors or decoy- receptors
Induce chemotaxis - Virus dissemination
Block chemotaxis (e.g., chemokine scavenging) - Survival of infected cells

Virus-encoded chemokine binding proteins
Block interaction with GAGs and/or chemokine receptors

Regulation of chemokine processing
Protease modulating proteins

Viruses interfere with chemokine receptors and ligands via

Cytokine homologs
Chemokine decoy receptors
Chemokine-binding proteins
Putative chemokine-processing proteases
Viral chemokine and chemokine receptor homologs

Alternative methods of virus mediated interference is through, inhibition of _______ ________ by _______ _______ that inhibit chemokine interaction with proteoglycans

chemokine oligomerisation secreting proteins

MHC Class I assembly and transport (1,2,3)

Epitopes need to be presented to viral - adaptive immune Virus enters cell -> some directed to proteasome -> broken down into peptides -> form complex with calretilculin, TAP1 and TAP2 -> introduced to MHC Class 1 groove -> enters Golgi -> transported to cell membrane -> acts as flag for Tc cells specific to this epitope

HIV nef protein down regulates…

Down-regulates MHC expression on infected cells - diminishes adaptive immune response Redistributes CD80 and CD86 away from cell surface in APCs - Functionally significant - Compromises activation of naïve T cells

Measles virus immune suppression x5

Reduction of ability of T cells to proliferate - secondary infections - compromised immune system Lymphocyte apoptosis lymphopenia Impaired lymphoproliferation Immunomodulatory cytokines - Increased IL-10 and IL-4 => dampens immune response IL-12 downregulation =>modulates immune response Impaired ability of immature DCs to mature - impaired antigen presentation - decreased differentiation

Species-specific PBMC proliferation reduction by RSV

Human PBMC stimulated by PHA -> proliferate hRSV F - massive reduction in proliferation - block proliferation of T cells Bovine PBMC stimulated by PHA -> proliferate bRSV F - massive reduction in proliferation - block proliferation of T cells Human blocks human. Bovine blocks bovine. DO NOT CROSS. No species cross over => species specificity

When do we need to modulate lymphocyte clonal expansion?

Poor memory T cell pool Poor recall responses to re-infection

Virus interference in the regulation of the chemokine network (1-6)

1) Cytokines control expression of chemokine receptors and chemokine secretion 2) Secereted chemokines - bind to chemokine receptors - activate intracellular signaling pathways 3) A gradient of monomeric chemokines induce chemotaxis of receptor-bearing cells 4) Chemokine oligomerization on cell-surface glycsoaminoglycans - leukocyte arrest 5) Secreted chemokines are scavenged by decoy- receptors. Can induce or block Chemotaxis 6) Alternatively, processed by proteolytic enzymes - generates peptides that have neutral, antagonistic or agonistic effects on chemokine receptors.

What is IRF-3?

A transcription promoter

Measles

4 days to 4 weeks Most infective disease known to humans 0.1-1%die Sequelae: sub-acute sclerosis encephalitis 7-10years post-infection => fatal