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Immunology terms
IMMUNE RESPONSE TO VIRAL INFECTION • Antigen, antibody, T-cells receptor • Phagocytosis • MHC (major histocompability complex) class I and II • Antigen presentation OUTLINE • Inflammation response Immune system • Immunological cells: Innate immune response • T and B-lymphocytes, NK cells and CTL (cytotoxic T-cells) • Macrophages Adap ve immune response • PMNs (neutrophils, leucocytes) Viral evasion from immune response • Complement system • Chemotaxis (IL, cytokines) • Apoptosis/ Autophagy • Clonal selection and expansion
Innate immune system, viral infec on Innate immune system---Recogni on
• Physical barriers (skin, mucosa, pH, enzymes) Pattern recognition receptors (PRRs)
• Innate (non-specific, early, first line of defense) Toll-Like receptors (TLRs) TLR2 measles CMV pattern recognition receptors TLR 3 (dsRNA) DNA/RNA viruses (intracellular) TLR 4 (RS viruses) quick response (min- hours after inf) TLR 7 (ssRNA) RNA viruses TLR 8 (ssRNA) (intracellular) Macrophages, dendritic cells, NK cells, PMNs TLR 9 (un-met CpG oligoDNA) DNA viruses (leukocytes) complement Retinoic acid inducible gene like receptors (RLRs) RIG-I (RNA viruses, paramyxoviruse, VSV, influenza, HCV) • Adaptive (acquired-,specific-, late, second line of defense) MDA5 (picornaviruses, reoviruses Specific antigen recognition LGP2 • Humoral (B-cells and antibody) • Cell mediated immune response (T-cells) Nuleotide oligomeraxation domain NOD receptors (NLRs) • Memory cells (both B and T cells)
Innate immune response---the first stage of defense Innate immune response---the first stage of defense
Nature Reviews Immunology 8, 911-922
(December 2008) | doi:10.1038/nri2436
Stephane Chevaliez et.al.
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Innate immune response---the first stage of defense Innate immune response---the first stage of defense
NK cells
At viral infection: IFN (alpha/beta/gamma) Cytokine production including: dsRNA IFNγ TNFα
Protein kinase R 2´5´oligo A synthase Ribonuclease L Activated protein Induce apoptosis via the TNFR Activation of 2´5´A kinase R (PKR) receptor synthase Activated Induce Fc receptor mediated cell Ribonuclease L death Inactivation of Activation of phagocytic/antigen Initiation factor (eIF-2) 2´5´oligo A presenting cells
mRNA dagradation Inh protein syntesis
Innate immune response---the first stage of defense Adap ve immune system--- cell-mediated immune response
Macrophages/Dendritic cells T- lymphocytes, processed antigen
CD8 +, CTLs Nature Reviews Immunology 8, 958-969 (December 2008) | doi:10.1038/nri2448 Ag recognition via MHC class I presentation 8-10 aa All types of cells => induce apoposis (intracellular ag incl virusis)
CD4+, T-helper Ag recognition via MHC class II 13-17aa professional ag presenting cells Cytokine production => IFNγ, TNFα + other pro-inflammatory Activate Adaptive TNFa, IFNg, IL-1, IL-IL6 cytokines, aid B-cell activation => ab production, memory cells immune response IL-12, IL-8
Adap ve immune system--- cell-mediated immune response Viral Evading host response (anti-innate immune level)
B-Lymphocytes Recognize small epitopes via its membane bound IgM molecule. Binding induce activation to a antibody producing” factory” = plasmacells
Antibody in viral defense includes: Neutralization, complement activation, opsinization and ------
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Viral Evading host response (anti-innate immune level) Viral Evading host response (anti-apoptosis)
• Extrinsic pathway => Casp 8=> Casp 3=>apoptosis • Intrinsic pathway (mitochondiral pathway) inactivation of IAP=> activation of VA RNA : caspases=> apoptosis •160-170 nt Virus Activated FasL/ PRR DNA damage TNFR •VA RNA I, II Death domain •Suppress IFN effects signaling IFN HPV E6, Ad E1B55K •Processed forms p53 PK (miVARNA) can p53 Ub HIV, Nef VA RNA R target cellular mRNA eIF2 Initates α transla on Proteosome apoptosis degradation VA RNA rescues IFN-hampered transla on apoptosis
Viral Evading host response Viral Evading host response Interfereing with MHCI antigeng presentation Interfereing with MHCII
Inh of transcription - Tat protein (HIV), competes with cellular DNA Antigen Translocation Activation of transactivation complex translation to loading to to cytoplasmic CTL MHC + β2 MHC (ER) membrane - E1A (Adeno), inh interaction with cAMP and CREB micro in IFNg mediated regulated protein induction Alter MHC trafficing – Glyko-Prot B (HSV), comp with ag-pept for binding to MHC and prevent MHC to reaching the cell surface Repressing cellular Inh proteasomal Retination in ER Viral proteins in Nef (HIV) blocks pept loaded MHC to reach surface and gene promoters degradation of (HCMV) complex with MHC promotes the immature to be exposed instead viral proteins inh recognition US2,US3 (HCMV) => proteasome degradation HIV (Tat), HPV (E5/E7) (EBV,EBNA-1) Re-direct MHC to (MCMV) proteasome degr. TCR interaction – gp42 (EBV) physical hindering the interaction with the T- Blocking TAP HIV (Nef)( HerpesV) cells receptor on CD4+ cells function gp120 (HIV-1) binds CD4 and interfere with CD4 MHC Blocking transport HCMV class II interaction ER-golgi (MCMV) Degradation of PLC (peptide Prevent terminal loading compl glycosylation, no HCMV export (Adeno) Iannello et al, Journal of Leukocyte Biology, Vol 79, Jan 2006
Viral evading host response NK cell response
! Gene/product! Function! ! Cowpox!virus! P35$ Chemokine$binding$protein$ Ectromelia!virus!! P13$ Binds$IL818,$blocks$IFN8γ$expression$ HCMV! UL816$ Prevents$NKG2D$recognition$ ! UL818$ Binds$inhibitory$LIR81$rec$ ! US828$ Sequester$CC$chemikines$ ! UL840$ Loads$HLA8E,$Maintains$HLA8E$on$inf$cells$ ! UL8142$ Decrease$MICA$ Hepatitis!B!! HBsurface$AG$ Decrease$number$of$NK$cells,$activation,$TRAIL$expression$ Hepatitis!C! E2$ Binds$CD881,$Decrease$IFN8g,$impairs$cytotoxic$granule$release$ ! Hep$C$core$prot$ Increase$MHC81$expression$ ! Core$35844$ HLA8E$stabilize$ HIV! NEF$ Decrease$HLA8A8B,$maintains$HLC8C8E,$Decrease$MICA,$ULBP82$ ! P24$ Stabilize$HLA_E$expression$ HPV! E6,E7$ Antagonistic$binding$of$IL818Ra,$Binds$IL818,$blocks$IFN8γ$ expression$ Kaposi´s!Sarcoma! K85$ Down$regulates$expression$B782,$ICAM81$ Herpes!Virus! MCMV! Gp40$ Down$regulates$surface$expression$RAE81$glycoproteins$ ! M131/129$ Chemokine$homologue,$inhibits$NK$function$ ! M144$ MHC81$mimic$ ! M155$ Down$regulates$H60$ ! M157$ Binds$inhibitory$Ly49I$receptor$in$sensitive$129/J$mice$
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