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Host Defenses Against Pathogens Innate immune responses: Occur early after infection Are not specific for the invading pathogen Do not induce memory Include cytokines (esp. interferon) and natural killer cells Adaptive immune responses Require time to develop Are specific for the invading pathogen Give rise to immunological memory, making vaccination possible Two arms: B cells (humoral immunity) and T cells (cellular immunity) Mechanisms of Innate and Acquired Immunity Innate Immunity Immune System Players Complement Cascade Natural Killer Cells Macrophages Monocytes Eosinophils cytokines Neutrophils Acquired Immunity Pathogen/Antigen Immune System Players Immediate Effect Result Antigen Presentation Extracellular Antigens Bacteria, Viruses B Cell + TH2 Intracellular Antigens Cells infected with Viruses, Rickettsia, or Mycoplasma CTL + TH1 Soluble Antigen, Activated B Cell Cell killing by CTL’s Humoral Immunity Cell-Mediated Immunity Class II MHC Class I MHC Cytokines and Chemokines The cytokines are a family of >30 signaling proteins They are secreted by many cells and have important regulatory roles They play a very important role in regulating the immune system They are components of both the innate and adaptive systems They include the IFNs, many interleukins, TNF, among others Most are about 30 kDa in size The chemokines are a family of >30 small proteins, 70-80 aa in length Some are constitutive, others are induced Some are proinflammatory They attract leukocytes and serve to maintain, e.g., lymph nodes, to attract immune cells to sites of inflammation, and other roles Interferons There are two classes of interferons, which use different receptors IFNs a and b use the same receptor and are called Type I IFNs These are secreted by most cells IFN g uses a different receptor It is secreted by T-cells and is called immune IFN Type I and II IFNs have overlapping but nonidentical effects IFNs induce the transcription of many genes They regulate the immune system They induce the anti-viral state in which cells are resistant to viruses They are extremely important for the control of viral infections In the absence of IFN, most viral infections are much, much more serious Characteristics of the Interferons Type I Type II IFN-a IFN-b Leucocyte IFN Fibroblast IFN Immune IFN All cells All cells T-lymphocytes Inducing agent Viral infection or ds RNA Viral infection or ds RNA Antigen or mitogen Number of species (number of genes) 14 (human) 22 (mouse) 1 1 Chromosomal location of gene 9 (human) 4 (mouse) 9 (human) 4 (mouse) 12 (human) 10 (mouse) Number of introns N one N one Three 165-166aa 166aa Size of IFN protein Receptors General functions Receptor for both IFN- a and INF-b consists of 2 polypeptides, IFN-aR1 and IFN- aR2, encoded on chromosome 21(human) or 16 (mouse) Anti-viral activity Anti-viral activity MHC Class I MHC Class I 146aa, dimerizes Receptor consists of 2 proteins: IFN-gR1 encoded on chromosome 6 (human) or 10 (mouse) and IFN-gR2 encoded on chromosome 21 (human) or 16 (mouse) Macrophage activation MHC Class I MHC Class II on macrophages NK cell activation Some anti-viral activity MHC Class II on B-cells Produced by Alternative name IFN-g IgE, IgG production by B-cells Genes Induced by Interferons Protein Induced by IFN-a (2’-5’) (A n ) synthetase +++ p68 Kinase (PKR) +++ Indoleamine 2,3-dioxygenase IFN-b IFN-g Inducible Element Functions/phenotype + ISRE (2’-5’) (A n ) synthesis Induction of anti-viral state esp. anti-picornavirus +++ + ISRE Protein Kinase Induction of anti-viral state + + +++ Tryptophan degradation g56 + + +++ Trp-tRNA synthetase GBP/ g57 + + +++ Guanylate binding MxA +++ +++ + Inhibits replication of IRF1/ISGF2 ++ ++ ++ Transcription factor IRF2 ++ ++ MHC Class I +++ +++ +++ (also dsRNA) MHC Class II Transcription factor +++ ++ RING 12 +++ RING 4 +++ +++ b2-microglobulin +++ +++ influenza and Upregulation of antigen presentation not ISRE nor GAS Upregulation of antigen presentation Proteosome subunit Putative TAP +++ MHC light chain VSV Signal Transduction by Interferons INF-g INF-a INF-gR1 INF-aR1 INF-aR2 INF-gR2 INF-g INF-a TYK2 JAK2 JAK1 JAK1 Recruitment STAT2 STAT1 STAT1 STAT1 Phosphorylation Dimerization p48 ISRE GAS NUCLEUS Phosphorylation ISRE Interferon Stimulated Response Element Protein-protein interactions GAS IFN- Gamma Activation Site Interaction resulting in phosphorylation Migration to nucleus Transcription initiation Development of the antiviral state Induction by IFN Latent 2’-5’ OS Latent RNase L Latent PKR dsRNA ACTIVATION ACTIVATION 2’-5’ OS RNase L PKR SYNTHESIS 2’-5’A PHOSPHORYLATION EIF2 EIF2 NUCLEUS HOST CELL Ribosome Phosphate group ds RNA EIF2 Phosphorylated EIF2 Activated RNase L Cells in the Antiviral State inhibit Viral Replication EIF2 TRANSLATION INITATION BLOCKED Uncoating Viral mRNA RNaseL VIRAL mRNA DEGRADED NUCLEUS NO VIRAL REPLICATION Ribosome Phosphate group ds RNA EIF2 Phosphorylated EIF2 Activated RNase L Effects of IFNs IFNs induce the antiviral state in which viral RNA cannot be translated The inducer of Type I IFNs is usually double-stranded RNA Double-stranded RNA is also required for the activity of the induced enzymes RNase L and PKR Thus, dsRNA plays a pivotal role in IFN action IFN has toxic effects and tight regulation of its action is necessary IFNs are also powerful regulators of the adaptive system They activate many types of immune cells They upregulate production of MHC and of other proteins required for function of the adaptive system Therapeutic Uses of some Cytokines Functional Group Name (Abbreviation) Antiviral cytokines Type I Interferon (IFN- ab Inhibits viral replication Type II interferon IFN- Inflammatory cytokines Tumor necrosis factor (TNF) Interleukin 1 (IL-1) Regulators of Lymphocyte Functions Normal Biological Function g Inhibits viral replication, upregulates expression of class I and class II MHC, enhances activity of macrophages Cytotoxic for tumor cells, induces cytokine secretion by inflammatory cells. Costimulates T-helper cells, promotes maturation of B-cells, enhances activity of NK cells, attracts macrophages and neutrophils Interleukin 6 Promotes differentiation of B cells, stimulates Ab secretion by plasma cells Interleukin 2 Induces proliferation of T-cells, Bcells, and CTLs, stimulates NK cells Interleukin 4 Stimulates activity of B cells, and proliferation of activated B-cells, induces class switch to IgG and IgE Interleukin 5 Stimulates activity of B cells, and proliferation of activated B-cells, induces class switch to IgA Interleukin 7 Induces differentiation of stem cells, increases IL-2 in resting cells Interleukin 9 Mitogenic activity Interleukin 10 Suppresses cytokines in macrophages Induces differentiation of T-cells into CTLs Interleukin 12 Interleukin 13 Regulates inflammatory response in macrophages Transforming growth factor (TGF- b Chemotactically attracts macrophages, limits inflammatory response, promotes wound healing Therapeutic targets Side effects of Therapy Chronic hepatitis B, hepatitis C, herpes zoster, papilloma viruses, rhinovirus, HIV(?), warts Fever, malaise, fatigue, muscle pain Toxic to kidney,liver,heart, bone marrow Lepromatous leprosy, leishmaniansis, toxoplasmosis As above for Type I interferons Anti-TNF in septic shock Shock with marked hypotension Receptor antagonist in septic shock ??? Leprosy, local treatment of skin lesions Vascular leak syndrome, hypotension, edema, ascites, renal failure, hepatic failure, mental changes and coma Septic shock Septic shock Symptoms similar to those for IL-2, especially shock and hypotension Natural Killer Cells NK cells are a first line of defense against viral infection They increase in activity in the first 2-3 days after infection and then decline They kill virus-infected cells, probably because these cells display too little class I MHC A deficiency in NK cells results in more serious viral infections Complement The complement system consists of >20 blood proteins It is activated by a proteolytic cascade It is a component of both the innate and adaptive immune systems It can interact with antibody to kill viruses or infected cells It can also kill pathogens in the absence of antibody One group of effector molecules inserts into membranes to kill cells or viruses Other effectors control pathogens in other ways Complement is a potentially destructive system and its activity must be carefully regulated Apoptosis Apoptosis is a cell suicide pathway in which mitochrondria cease to function, DNA is degraded, and the cell fragments into small pieces Apoptosis is non-inflammatory Many events can trigger apoptosis, including stress of viral infection, withdrawal of growth factors, or a deregulated cell cycle CTLs kill target cells by inducing apoptosis Proteases called caspases are key players in the apoptotic pathway By undergoing apoptosis, an infected cell prevents further production of virus Mechanisms of Apoptosis Killling via Receptor Killing due to External Stimuli Hypoxia Ligand FASL Viral infection E2F Uv irradiation Unscheduled DNA synthesis p53 Receptor Killing by CTL via the Granzyme B Pathway Mdm2 Fas CTL p53 Perforin Channel Bax Granzyme ?? DD DD DD Cytoplasmic death domains FADD Activation cleavages DED DED DED DED Bcl-2 Death effector domains Procaspase Procaspase Procaspase Caspase cascade Caspase cascade Caspase cascade Effector caspases Induction Inhibition Apoptosis The Adaptive Immune System--CTLs The cellular arm of the adaptive immune system consists of CTLs (cytotoxic T lymphocytes) that kill infected cells Most CTLs express CD8 and respond to antigen presented by Class I MHC (major histocompatibility complex) molecules CTLs recognize the antigen-MHC I complex by means of a Tcell receptor that they express on their surface Activation of CTLs requires exposure to cognate antigen and a second signal, usually supplied by T-helper cells Upon activation, CTLs express IFN-g and other proteins and begin to divide; they are programmed to undergo apoptosis once the cognate antigen is withdrawn Upon activation, memory T-cells are formed that persist and that are programmed to respond rapidly upon renewed exposure to antigen T-Helper Cells TH cells express CD4 and recognize antigen presented by Class II MHC Whereas MHC Class I is expressed by most cells in the body, Class II is expressed primarily by T-cells, B-cells, and other cells of the immune system TH cells secrete cytokines that help CTLs or B-cells to become activated A spectrum of TH cells exists that secrete different assortments of cytokines and that preferentially help CTLs or B-cells The effector cells of the adaptive immune system require at least two different inputs to become activated, thus subjecting this potentially harmful system to greater control A. Class I MHC a1 b2m S S S S S Class II MHC a2 a1 a3 S a2 S S S S S Plasma membrane Cell cytoplasm B. Peptide-binding cleft a1 domain a2 domain b2 microglobulin a3 domain S b1 b2 Structure of the T-cell receptor (TCR) a or g chain b or chain NH 2 NH 2 S S S S S S S S Variable regions Constant regions S S Plasma membrane Cell cytoplasm TM COOH COOH Interaction between a cell expressing MHC Class I and a CD8+ T cell Interaction between an Antigen-presenting Cell expressing MHC Class II and a CD4+ T cell. Antigen-presenting cell Almost any host cell S CD8 dimer S S S S S S S S S S S S MHC Class I S S MHC Class II S Antigenic peptide S S S S a chain S S Antigenic peptide S CD4 S S b chain S TCR a chain S S S S S S S S S S S S S S S-S Cytotoxic CD8 + T cell b chain S-S CD4 + Helper T cell TCR Figure 8.4 Germline a-chain DNA 5’ Va1 Van V1 Vn D1D2 J J C JaJa Jan 3’ Ca V-J Joining Va Ja Jan Ca 3’ Vb 5’ Rearranged b-chain DNA Vb1 Jb D b Cb Vb Db Jb C b Transcription mRNA splicing Translation Jb C b Db2 S S-S S S Protein product heterodimer S NH 2 NH 2 Va Ja Ca S Transcription mRNA splicing Translation S Rearranged a-chain DNA Va2 S Va1 S 5’ 3’ Vb14 V-DJ joining D-J joining 5’ Germline b-chain DNA Vb1 Vbn Db Jb C b Db 2 Jb C b Vb14 3’ Comparison of Diversity in Human Immunoglobulin and T-Cell Receptor Genes Mechanis m of Diversity a b T-Cell Receptors Immunogobulins Heavy Chains Light Chains chain chain g T-Cell Receptors a chain b chain g chain chain Multiple germ-line gene segments V 65 40 30 ~70 52 12 >4 D 27 0 0 0 2 0 3 J 6 5 4 61 13 5 3 65 X 27 X 6= 1.0 X 104 40 X 5 = 30 X 4 = 70 X 61 = 12 X 5 = 4X3X 3= 200 120 ~ 430 52 X 2 X 13 = 1.3 X 103 60 36 rarely --- --- --- often --- --- 2 1 ?? ?? Combinatorial Joining Combinatorial V-J-D combinations D segments read in 3 frames Joints with N and P nucleotides V gene pairs Junctional Diversity Total Diversity 2 (1) 1.0 X 104 X 320 = 3.2 X 106 430 X 1.2 X 103 = 5.8X 106 60 X 36 = 2.1 X 103 ~3 X 107 ~2 X 1011 ??? ~ 10 14 ~ 10 18 ??? Antigen Processing by Class I and Class II MHC Infected cell External antigen or pathogen or Viral protein synthesized in the cell NUCLEUS a A Proteasome b Acidic vesicle B c ER TAP C D d e (Invariant chain peptide) E MHC Class I MHC Class II Adaptive Immunity--B cells The humoral immune response is carried out by B cells B cells express anchored antibody on their surface Upon exposure of the cell to an antigen recognized by the antibody, the cell can divide and produce plasma cells that secrete antibody Activation of the B cell requires a second signal supplied by TH cells After activation, memory cells are formed that persist and are capable of more rapid activation upon exposure to cognate antigen Secreted antibodies are of 5 different kinds which have different functions in the immune response The Immunoglobulin Fold CL domain b strands V L domain Loops C-terminus Disulfide bond N-terminus HV regions Structure of an Immunoglobulin G Molecule Variable regions Antigen binding domain VL S S S S S S S CL S S S Heavy Chains S S S S S VH S S S S S Constant S S S S S C H1 S Variable Hypervariable (CDR’s) VH or VL S S S S S S S S C H2 Effector function domain C H3 S CDR2 S S Light Chains Constant CDR1 CDR2 CDR3 Hinge Light chain variable region CDR1 H Variable Hypervariable (CDR’s) Heavy chain variable region DH JH JL CDR3 S Structures of the Different Classes of Secreted Immunoglobulins IgG IgD IgE VL VL V H CL VL VH C L V H CL C g1 C 1 C 1 SS SS SS SS C g2 C 2 C 2 C g3 SS C 3 C 3 C 4 SS IgA dimer IgM pentamer VL VL V H CL V H CL C 1 C a1 SS SS SS C 2 C a2 C 3 C a3 SS ss ss C 4 S S S S ss ss SS SS SS g a SS Types of Secreted Antibodies IgM is the earliest antibody secreted by a plasma cell. It is a sign of recent infection. IgG is long lived and circulates in the blood for years. Many cells in the body are thus exposed to it. It is also transferred to the fetus of a pregnant woman and is responsible for maternal immunity. IgA is secreted on mucosal surfaces and if effective against viruses that replicate in the respiratory tract or the intestinal tract IgE is most effective against large parasites and is responsible for the symptoms of hay fever when it reacts against pollen grains, mites, dust particles, or other large objects IgD is only expressed together with IgM. Its precise role in immunity is not clearly understood. Formation of the Human Immunoglobulin Heavy and Light Chains A. Light Chain Germline chain DNA 5’ L V1 V23 J Vn C 3’ V-J Joining 5’ L V1 Rearranged -chain DNA V J J C 3’ Transcription, RNA splicing, polyadenylation 3’ Cap (An) IgM Translation Light Chain ( ) protein Ck SS Vk Heavy Chain ( ) protein VH C1 C2 C3 SS Light Chain ( ) mRNA C LV J 5’ C4 Translation 5’ Heavy Chain ( ) mRNA L V DJ C (An) Cap 5 3’ Transcription, RNA splicing, polyadenylation 5’ L V1 V179 3’ V DJ JH Rearranged H-chain DNA V-DJ joining 5’ L V1 V180 Vn 3’ D H 1 D H 6 DJ JH D-J joining Germline H-chain DNA 5’ L V1 B. Heavy Chain Vn D H 1 D H 7 D H 13 JH C C C g3 Cg1 Cg2b Cg2a C Ca 3’ Comparison of Diversity in Human Immunoglobulin and T-Cell Receptor Genes Mechanis m of Diversity a b T-Cell Receptors Immunogobulins Heavy Chains Light Chains chain chain g T-Cell Receptors a chain b chain g chain chain Multiple germ-line gene segments V 65 40 30 ~70 52 12 >4 D 27 0 0 0 2 0 3 J 6 5 4 61 13 5 3 65 X 27 X 6= 1.0 X 104 40 X 5 = 30 X 4 = 70 X 61 = 12 X 5 = 4X3X 3= 200 120 ~ 430 52 X 2 X 13 = 1.3 X 103 60 36 rarely --- --- --- often --- --- 2 1 ?? ?? Combinatorial Joining Combinatorial V-J-D combinations D segments read in 3 frames Joints with N and P nucleotides V gene pairs Junctional Diversity Total Diversity 2 (1) 1.0 X 104 X 320 = 3.2 X 106 430 X 1.2 X 103 = 5.8X 106 60 X 36 = 2.1 X 103 ~3 X 107 ~2 X 1011 ??? ~ 10 14 ~ 10 18 ??? Time Cours e of Primary and Secondary Antibody Respons es Antibod y concentration in seru m un its/ml 100 Total 10 Primary Response 1 Secondary Response Total IgG 0.1 IgM IgG IgM 1° Antigen 2° antigen Time after Immunization Immunoglobulin Class Switching To Produce Heavy Chains For IgG And IgE 5’ C V DJ C C g3 Cg1 Cg2b Cg2a C 3’ Ca H-Chain DNA S Sg3 Sg1 Sg2b Sg2a Cg1 V DJ Class-switched H-chain DNA Cg2b Sg2b Cg2a Sg2a C S Transcription, splicing, polyadenylation C g1 Cap Sa Recombination between S C 3’ Translation Ca Transcription, splicing, polyadenylation 5’ 3’ C V DJ Cap An SS SS SS Translation IgG heavy chains g1 and S Sa An SS SS IgG1 mRNA V DJ 3’ Ca V DJ JH 5’ Sa and S g1 Recombination between S 5’ S IgE heavy chains IgE mRNA Cytokine Networks Important for Innate and Acquired Antiviral Immune Responses Endothelial cell MCP-1 CD4+ T-cell IL-1b TNF- a IL-6 IFN- ab CD8+ T-cell IL-15 IL-18 Macrophage dendritic cell IL-12 Cytotoxic T Lymphocyte (CTL) IFN- g LT-a Natural Killer cell (NK) Th1 IFN-g IL-2 LT-a Th2 B-cell IL-4 IL-5 IL-10 IL-13 IgM IFN- g Cell-mediated response to viral infection Plasma Cell IgG Developmental pathway Secretion IgA Activation Inhibition IgE Humoral response to viral infection Control of the Immune System and Autoimmunity T-cells are negatively selected during development if they recognize self Activation of B-cells or T-cells requires two signals, exposure to the cognate antigen and cytokine stimulation from TH cells An inflammatory response induced by infection is important for optimal signaling and activation After activation the cells die off when the cognate antigen is no longer present in sufficiently high concentrations Failure of these control mechanisms can result in autoimmunity, which can lead to very serious illness Vaccines The existence of memory in the adaptive immune system makes it possible to immunize people by vaccination Vaccines may be attenuated viruses that infect but do not cause disease, inactivated viruses that cannot infect but which expose the person to the viral antigens, or subunit vaccines that contain only a subset of viral proteins Attenuated vaccines usually are the most effective, but it can be difficult to balance sufficient attenuation so as not to cause disease in any individual with the necessity for sufficiently vigorous replication to induce immunity Inactivated or subunit vaccines require that large amounts of protein be injected and it may be difficult to obtain an inflammatory response required for a vigorous response without overdoing it Vaccines (con) The take of live virus vaccines can be interfered with by concurrent infection with another virus, which is not a problem with inactivated virus vaccines Live virus vaccines are less stable than inactivated vaccines Inactivated virus vaccines require large amounts of material, multiple injections, and give less solid immunity Some candidate inactivated virus vaccines have given unbalanced responses that resulted in potentiating more serious illness upon subsequent infection by the virus rather than in immunity to the virus Characteris tics of Anti-viral Vaccines Live Attenuated Virus Currently Licensed Vaccines: Inactivated Virus and Subunit Vaccines Poliovirus (Sabin) Poliovirus (Salk) Measles Influenza Mumps Rabies Rubella Hepatitis B Yellow Fever Hepatitis A Vaccinia Japanese encephalitis Varicella-Zoster Western equine encephalitis (experimental) Rotavirus* Adenovirus (in military recruits) Junin (Argentine hemorrhagic fever) In addition, live attenuated vaccines for the following viruses are close to release to the public: human cytomegalovirus, hepatitis A, influenza, dengue, human parainfluenza, and Japanese encephalitis * withdrawn Characteristics of the Immune Response after Vaccination Type of Vaccine Live Attenuated Virus Inactivated Virus and Subunit Vaccines Antibody induction (B-cells) +++ +++ CD8 + cytotoxic T-cells +++ - CD4 + helper T-cells +++ +++ Reactivity against all viral antigens Usually Seldom Longevity of immunity Years/decades Months/years Cross-reactivity among viral strains +++ + Risk of viral disease + - Many Vaccines Have Been Successful in Controlling Viruses Smallpox has been eradicated Poliovirus is on the verge of being eradicated Good vaccines exits for mumps, measles, rubella, yellow fever, tickborne encephalitis, and other viruses However, it has not yet been possible to develop vaccines against some viruses, such as HIV and RSV Although a good vaccine against measles exists, it has not been possible to eradicate the virus because infants in some developing countries become infected with the wild-type virus as soon as maternal immunity is lost Worldwide Incidence of Measles as of August 1998. Kuwait Equator Cases of Measles per 100,000 Population >100 10-100 1-10 None No data Worldwide Immunization Coverage for Measles as of August 1998. K u w ai t Vaccine Coverage for Meas les Low, <50% vaccinated Medium, 50-80% vaccinated High, >80% vaccinated No data Equator Child Mortality after High-Titer Measles Vaccination in Senegal 200 Mortality (per 1000 Children at 5 Months) EZ-HT 150 SW-HT 100 Standard 50 0 5 10 15 20 25 Age (Months) 30 35 40 Major Strategies used by Viruses to Evade the Immune System Rapid shutdown of host macromolecular synthesis Evasive strategies of viral antigen production Restricted gene expression; virus remains latent with minimal or no expression of viral proteins Infection of sites not readily accessible to the immune system Antigenic variation; antigenic epitopes mutate rapidly Interference with MHC Class I Antigen Presentation Downregulation of transcription of MHC class I molecules Degradation of MHC class I molecules Retention of MHC class I molecules within the cell Downregulation of transcription of TAP Interference with the activity of TAP Interference with natural killer (NK) cell function Interference with MHC Class II Antigen Presentation Interference with antiviral cytokine function Production of viral homologues of cellular regulators of cytokines Neutralization of cytokine activities Inhibition of the function of Production Inhibition of Apoptosis IFN of soluble cytokine receptors Adenoviruses Inhibit Antigen Presentation by Class I MHC Molecules Proteosome (Inhibits transcription of TAP mRNA) E1A Nucleus TAP E1A (Inhibits transcription of class I molecules) TAP ER E3-19K (Keeps class I molecules in ER) Inhibition by Ad2 MHC class I molecules Inhibition by Ad12 Herpesviruses and Antigen Presentation by Class I MHC Molecules EBNA-1 (Protein not processed) Proteosome Nucleus (Blocks transport US6 by TAP) TAP Acts on TAP (Blocks transport by TAP) US2, US11 (Causes MHC molecules to be degraded) ICP47 (Binds to b2 microglobulin) ER UL18 US3 (Keeps class I molecules in ER) Interference by HCMV MHC Class I Interference by HSV Interference by EBV Some Viruses that Alter Antigen Presentation by Class I MHC Molecules Interference level Virus Family Virus Virus Protein Mechanis m Downregulation of MHC class I expression at cell surface Adenoviridae Ad 2 E3-19K Ad12 E1A Viral protein binds to class I molecules and keeps them in the ER Inhibits transcription of class I mRNA HCMV US2, US11 HCMV UL18 Gene products lead to degradation of class I molecules Binds to b2 microglobulin Picornavirus FMDV ?? Downregulation of class I protein at the surface of cells Lentivirus HIV Tat Nef Inhibits transcription of MHC class I mRNA Downregulates surface expression of class I proteins Adenoviridae Ad12 E1A Inhibits transcription of TAP1 and TAP2 Herpesviridae HSV ICP47 Binds to TAP and prevents transport of antigenic peptide to MHC class I HCMV US6 Blocks transport by TAP EBV EBNA-1 EBNA-1 protein with Gly-Ala repeat is not processed by proteasome HepB Ag epitopes Epitopes mutate so that they are no longer recognized by CTLs Herpesviridae Alteration of antigen processing Alteration of spectrum of antigens presented Hepadnavirus Ad12 = adenovirus 12; HCMV = human cytomegalovirus; FMDV = foot and mouth disease virus; HIV = human immunodeficiency virus; HSV = herpes simplex virus; EBV = Epstein-Barr virus; HepB = hepatitis B virus. Inhibition of Apoptosis by Adenoviruses DNA Viruses that Interfere with Apoptosis Virus Family Viral Protein Mode of Interference Cowpox Vaccinia Myxoma crmA SPI-2 M11L, T2 Molluscum contagiosum M159, 160 Serpin homologue, inhibits proteolytic activation of caspases crmA homologue, inhibits activation of caspases T2 is a homologue of TNFR, and inhibits interaction of TNA-a with TNFR; M11L has a novel function Has death domains like FADD, inhibits FADD activation of caspase 8 Asfarviridae African swine fever virus LMW5-HL Homologue of Bcl-2 Herpesviridae herpes simplex herpes saimiri HHV 8 g34.5 gene Epstein-Barr (latent) LMP1 Prevents shutoff of protein synthesis in neuroblastoma cells Homologue of Bcl-2 Homologue of Bcl-2 vFLIPS, prevents activation of caspases by death receptors Upregulates transcription of Bcl-2 and A20 mRNAs; inhibits p53-mediated apoptosis Inhibits p53 activity; has some sequence similarity to Bcl-2 Poxviridae Virus (lytic) HCMV ORF 16 product KS bcl-2 K13 BHFR1 Downregulates transcription of p53 mRNA Gammaherpesvirinae IE-1, IE-2 viral FLIPs Polymaviridae SV40 Large T antigen Binds to and inactivates p53 Papillomaviridae HPVs E6 Binds to p53 and targets it for ubiquitin-mediated proteolysis Adenoviridae Adenovirus E1B-55K E3-14.7K E3 10.4 K/14.5 K E4 orf 6 E1B 19K Binds to and inactivates p53 Interacts with caspase-8 Blocks caspase 8 activation by destruction of Fas Binds to and inactivates p53 Functional homologue of Bcl-2; interacts with Bax, Bi, and Bak Baculoviridae AcMNPV p35 IAP Forms a complex with caspases; inhibits caspase-mediated cell death Like FLIPs, inhibits activation of caspases Hepadnavirus HepB pX Binds to p53 Inhibits signalling from death domains to caspases Virus Manipulation of Cytokine Signalling Virus Family Virus Cellular Target or Homolog Viral Factor Mode of Action Herpesviridae HCMV TNF receptor Chemokine receptors UL144 US28 Unknown function, retained intracellularly Competitive CC-chemokine receptor, sequesters CC-chemokines HHV-8 Type 1 IFNs Virus-encoded chemokines vIRF K9 vIRF-2 vMIP-I, vMIP-II Blocks transcription activation in response to IFN May m odulate expression of early inflammatory genes TH -2 chemoattractant, chemokine receptor antagonist HSV Type 1 IFNs RNase L g134.5 2’-5’ (A) Reverses IFN-induced translation block RNA analog, inhibits RNase L EBV Type 1 IFNs PKR Chemokine receptors IL-10 EBNA-2 EBER-1 BARF-1 BCRF-1 Downregulates IFN-stimulated transcription Blocks PKR activity Secreted, sequesters CSF-1 IL-10 homologue, antagonizes T H -1 responses Adenovirus Type 1 IFNs E1A Blocks IFN-induced JAK/STAT pathway PKR TNF-a VA 1 RNA E3 proteins Blocks PKR activity Various mechanisms Adenoviridae Hepadnaviridae HepB Type 1 IFNs Terminal protein Blocks IFN signalling Flaviviridae HepC PKR E2 Inhibits PKR activation in response to type 1 IFN Retroviridae HIV PKR TAR RNA Recruits cellular PKR inhibitor TRBP Poxviridae See Table 8.J Abbreviations: HCMV = human cytomegalovirus; TNF = tumor necrosis factor; HHV-8 = human herpesvirus eight (Kaposi’s); HSV = herpes simplex virus; IFN = interferon; PKR = ds RNA-dependent protein kinase; CSF-1 = colony stimulating factor; HIV = human immunodeficiency virus. Pox Defense Molecules System Target Virus Gene Homolog Properties Complement C4B and C3B Vaccinia Variola C3L D15L C48 binding protein 4SCRs, secreted,binds and inhibits C4B and C3B, virulence factor ? ? Vaccinia Variola B5R B6R Complement control proteins 4 SCRs, EEV class I membrane glycoprotein, for virus egress Type 1 IFN Vaccinia B18R IFN receptor Binds to and inhibits IFN- PKR Vaccinia Variola Swinepox K3L C3L K3L eIF-2a Binds PKR, inhibits phosphorylation of eIF-2a, IFN resistance dsRNA Vaccinia Variola E3L E3L PKR Binds ds RNA, nuclear localization inhibits activation of PKR, IFN resistance. IFN-g Myxoma Vaccinia Variola Swinepox T7 B8R B8R C61 IFN-g receptor Secreted, binds and inhibits IFN-g ICE Cowpox Vaccinia Variola crmA B14R B12R SERPIN Prevents proteolytic activation of IL-1 b, inhibits inflammatory response, inhibits apoptosis IL-1b Vaccinia Cowpox B15R IL-1 receptor Secreted glycoprotein, binds and inhibits IL-1b IL-8 IL-8 Swinepox Swinepox ecrf3 K2R IL-8 receptor Binds IL-8 TNF TNF-a,TNF-b Myxoma Vaccinia Variola Cowpox T2 G2R, (truncated) Crm B TNF receptor Secreted, binds and inhibits TNF-a, TNF-b Interferon IL-1 CCchemokines Myxoma Vaccinia Variola Cowpox p35 Chemokine receptor Secreted, binds to CC-chemokines SCR = 60 amino acid sequence called: ”Short consensus sequence”; EEV = extracellular enveloped virions; PKR = dsRNA-dependent protein kinase; IFN = interferon; SERPIN = serine protease inhibitor superfamily Adapted from Evans (1996) ; and a review by Tortorella et al (2000). a Pathogens and the Immune System The humoral system may have evolved to fight bacteria and the CTL system to fight viruses, but both are important for the control of any pathogen Humans cannot live without an immune system but this is the result of a long process of coevolution This coevolution required mutual adaptation Pathogens that are too virulent for their reservoir host become attenuated (e.g., rabbit myxoma virus) Pathogens that are effectively defeated by the immune system often evolve new tricks to get around it (e.g., counterdefenses evolved by herpes-, pox-, and adenoviruses) Hosts that cannot control their pathogens are removed from the gene pool in favor of variants that can (e.g., rabbits and myxomavirus)
