Pathogen interactions with cytokines and host defence: an overview

Veterinary Immunology and Immunopathology 63 Ž1998. 139–148

Pathogen interactions with cytokines and host defence: an overview Heng-Fong Seow

)

Macfarlane Burnet Centre for Medical Research, Yarra Bend Road, P.O. Box 254, Fairfield, Victoria 3078, Australia

Abstract This review summarises some of the immune evasion tactics adopted by pathogens. They include the antagonism of immune function through the use of homologues of cytokine receptors, expression of viral proteins which interact with cytokine signal transduction and expression of cytokine mimics and host proteins that influence the Type I or II cytokine responses. Some of the viral defense molecules that interfere with the functions of cytokines include the EBV protein BCRF1 Žviral IL-10. which blocks synthesis of cytokines such as IFN-g , viral IL-17 and IL-8 receptor encoded by the herpesvirus saimiri genome and chemokine receptor homologues of Epstein–Barr virus, herpesvirus saimiri and cytomegalovirus. These immunomodulatory tactics function to protect the host from the lethal inflammatory effects as well as inhibit the local inflammatory response elicited to kill the foreign pathogen. Other strategies include the alterations in cytokine expression such as demonstrated with the hepatitis B virus ŽHBV. core protein and terminal protein which can inhibit interferon-b gene expression, the interactions of the hepatitis C virus core protein to lymphotoxin-b receptor and the effects of the interferon signal transduction pathway by adenovirus EIA oncogene and HBV by reducing levels or activity of the cytosolic latent transcriptional factors ŽSTATS.. Immune evasive strategies of helminth parasites related to cytokine activities will also be briefly discussed. q 1998 Published by Elsevier Science B.V. All rights reserved. Keywords: Pathogen; Cytokines; Viral proteins; Herpesvirus saimiri; Epstein Barr virus; Cytomegalovirus

) Present address: Department of Medicine, Faculty of Medicine and Health Science, University Putra Malaysia, Serdang, 43400 Selangor, Malaysia. Tel.: q60 603 9486101; fax: q60 603 9426957; e-mail: [email protected]

0165-2427r98r$19.00 q 1998 Published by Elsevier Science B.V. All rights reserved. PII S 0 1 6 5 - 2 4 2 7 Ž 9 8 . 0 0 0 9 0 - 7

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1. Introduction Infectious pathogens have many tactics to avoid the immune recognition to ensure that, firstly, they can multiply, survive and persists in the host and, secondly, the host does not die from the lethal effects of the pathogen-induced inflammatory response. These tactics include the production of antigenic variants, inhibition of synthesis of host proteins such as major histocompatibility antigens ŽMHC., interference of the antigen processing pathway, inactivation of complement and antibody function, regulation of apoptosis Žreviewed by Spriggs, 1996., effects on cellular kinases ŽSen and Lengyel, 1992. and cell cycle progression ŽSchang et al., 1996.. This review will only focus on the interaction between pathogens with host cytokines. Many of the examples of evasive strategies come from the herpes Žreviewed by Davis-Poynter and Farrell, 1996. and poxvirus ŽAlcami and Smith, 1995. families. These viruses can establish long-life latency and persistence which is controlled by the host such that a balance is established between virus replication and host immune mechanisms and infection is maintained at subclinical level. The evasive strategies pertaining to those which counteract cytokine action include mechanisms which either block or bias the production of particular cytokines, mimicry of cytokine andror cytokine receptors and inhibition of cytokine release or action. Viral proteins have been shown to alter the transcriptional activation of cytokine gene expression as well as modify the cytokine response pathway by influencing the cell signal transduction pathways. Why is it important to gain knowledge in the immune evasion strategies adopted by pathogens? These studies will shed light on the biology of the interactions between host and pathogen and may lead to discovery of novel immunomodulatory proteins which may be useful immunotherapeutic agents. Further understanding of the mechanisms of immune evasion is important in order to develop strategic methods for the development of attenuated vaccines, for the construction of vectors, e.g. bacterial or viral vectors for gene and antiviral therapy. In addition, these studies will give further insight to novel immune effector mechanisms elicited in response to infection.

2. Cytokine and cytokine receptor mimics Many of the cytokine or their receptor mimics have been initially discovered by sequencing the virus genomes and then identifying the sequence similarities with host proteins that function in the immune system. Table 1 summarises the cytokine mimics encoded by various viruses and helminths. Perhaps, the best known and earliest example of viral immunomodulation is the effect of a viral protein from a g-herpesvirus, Epstein–Barr virus ŽEBV. known as BCRFI. In immunocompromised patients, primary infection of EBV results in acute B lymphoproliferative disease. In immunocompetent hosts, EBV persists in the B lymphoid system. Most of our knowledge of latent or lytic EBV infection in vitro is based on infection of B lymphocytes. IL-10 was first described as a soluble factor Žwith 70% amino acid identity to EBV BCRFI. that inhibited the production of IFN-g from T cell clones

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Table 1 Summary of cytokine mimics encoded by viruses or helminths Pathogen

Cytokine mimicked

References

Epstein–Barr virus BCRF1 Equine herpesvirus 2 Orf virus Herpesvirus saimiri HVS13 Herpes simplex virus type 6 Molluscum contagiosum virus Kaposi’s sarcoma-associated herpesvirus ŽKSHV. Fasciola hepatica Onchocerca ÕolÕulus

IL-10 IL-10 IL-10 IL-17 b-chemokine MIP-1 b IL-6 MIP IL-5-like factor C–C chemokine

Moore et al., 1990 Rode et al., 1993 Haig, 1996 Yao et al., 1995 Gompels et al., 1995 Senkevich et al., 1996 Moore et al., 1996 Milbourne and Howell, 1990 Erttmann et al., 1995

ŽMoore et al., 1990; Hsu et al., 1990.. Since that time, other IL-10 homologues have also been described in the equine herpesvirus 2 genome ŽRode et al., 1993. and orf virus ŽHaig, 1996.. IFN-g plays a pivotal role in influencing the development of Type I helper cells and the downregulation of IFN-g production by BCRF1 could result in inhibition of the appearance of Th1 cells. Further work showed that both human IL-10 and BCRF1 can inhibit antigen-specific proliferative response by T cells and act as growth factors for B cells Žreviewed by De Waal Malefyt et al., 1992.. The B cell growth activity of BCRF1 would be an advantage to EBV in view of the ability of EBV to transform human B cells. However, there are currently conflicting reports on the role of BCRF1 in infection and transformation of B cells ŽMiyazaki et al., 1993; Swaminathan et al., 1993.. T cells and natural killer cells were shown to inhibit infection and immortalisation of B cells by EBV via the action of IFN-g ŽThorley-Lawson, 1981; Lotz et al., 1985.. The BCRF1 gene is transcribed in the late phase of the EBV lytic cycles when viral proteins are actively synthesized and virus particles are produced. It is thus possible that BCRF1 may inhibit T cell and natural killer cell response that could be activated during the early stage of the infection by downregulation of IFN-g expression. Thus, expression of BCRF1 would assist EBV to escape the host immune surveillance system. In addition, EBV has other strategies for immune evasion. It can induce the expression of host proteins that play an important role in modulating the immune response. Two novel genes, EBI 1 and 2, predicted to encode for G-protein coupled peptide receptors ŽBirkenbach et al., 1993. and a third novel EBV-induced gene, EBI 3 ŽDevergne et al., 1996. were identified by subtractive hybridisation. EBI 3 had 27% identity to the p40 subunit of interleukin-12 ŽIL-12. and was found to be produced by EBV transformed B cells. It is thus predicted that the secreted EBI 3 could antagonise or modulate IL-12 heterodimer activity to alter the cytotoxic T and natural killer function, perhaps, by its ability to bind to p35 or compete with p40. This would facilitate the survival and initial expansion of latently infected cell pool. Further studies need to be performed to determine the biological activity of EBI 3. Herpesvirus saimiri is a T lymphotropic virus that causes T cell leukemias and lymphomas that is lethal in several non-human primates. It can also transform T cells into immortalised T cell lines in vitro. More recently, a viral protein encoded by herpes

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saimiri virus, HVS13, was found to contain 57% identity to human CTLA-8 or more recently known as IL-17 ŽRouvier et al., 1993; Yao et al., 1995.. Both HVS13 and IL-17 can stimulate IL-6 secretion, costimulate T cell proliferation, stimulate NFkb , a transcription factor that regulates a large number of gene products, e.g., activation of IL-6, TNF, IL-1 b and IL-2 receptor expression. It has been shown that proteins with oncogenic potential such as hepatitis B X gene, HTLV-1 Tax gene transactivate through NFkb resulting in uncontrolled T cell growth. It is thus possible that HVS13 binds to the IL-17 receptor on the host cells, signal is transduced resulting in triggering of oncogenesis and lethality to the host. The a and b family of chemokines are potent chemoattractants and can regulate the homing and activation of lymphoid and myeloid cells. Homologues of chemokines have been described for herpes simplex type 6 virus and a tumorigenic poxvirus, Molluscum contagiosum ŽMCV. by virtue of amino acid homologies ŽGompels et al., 1995; Senkevich et al., 1996.. The mimic protein encoded by the MCV gene had 27% homology to MIP-1 b , the general disulphide pattern and general structure of chemokines. However, it lacks the amino terminal region implicated in monocyte activation. Amino truncated analogues of C–C chemokines have previously been shown to bind to the receptor but do not have biological activity. Thus, this MCV protein is predicted to be a chemokine antagonist and could inhibit inflammation. More recently, four viral proteins similar to two macrophage inflammatory proteins ŽMIP., IL-6 and interferon-regulatory factor were found to be encoded by the Kaposi’s sarcoma-associated herpesvirus ŽKSHV. genome. The biological activity of viral MIP was found to be similar to human MIP, i.e. it inhibited the replication of HIV-1 strains which were dependent on the CCR5 co-receptor for viral entry ŽMoore et al., 1996..

3. Cytokine receptor mimics Chemokine receptors are members of the G-protein coupled receptor family with a characteristic seven transmembrane spanning region. This family of receptors also bind various ligands such as neurotransmitters, hormones and light. The receptor is coupled to trimeric GTP-binding proteins and transduce signals via phospholipase C and generates secondary messengers such as phosphatidylinositol phosphate ŽIP3. and diacylglycerol leading to increased intracellular calcium levels and activation of protein kinase C. Sequencing of the herpesvirus saimiri genome showed that ORFHVS 74 Žpreviously termed ECRF1. encoded a G-protein coupled receptor homologue with 30% homology with IL-8 receptor ŽNicholas et al., 1992.. HVS74 of herpesvirus saimiri was able to bind to IL8 resulting in increased intracellular calcium concentrations ŽAhuja and Murphy, 1993.. This suggests a novel role of a chemokines in the pathogenesis of HVS infection by G-protein coupled receptor signaling via the viral protein HVS74. It is probable that HVS74 and viral IL-17 ŽHVS13. could cooperate to downregulate the inflammatory response, i.e. viral IL-17 might stimulate the production of IL-8. IL-8 would then mediate effects through the viral G-protein coupled receptor, HVS74. Viral mimicry of chemokine receptors was also found in open reading frame US28 from human cytomegalovirus. US28 encodes a receptor for b family of chemokines

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Table 2 Summary of cytokine receptor mimics Viruses

Viral homologue

Host homologue

References

Shope fibroma Myxoma Myxoma Swine pox Vaccinia Vaccinia Variola Capripox Herpes saimiri Cytomegalovirus

T2 T2 T7 C6L B15R B8R B8R Q2r3L HVS74 US28

TNF-a R TNF-a R IFN-g R IFN-g R IL-1 b R IFN-g R IFN-g R chemokine R IL-8BR MIP-1 a rrantes R

Smith et al., 1991 Upton et al., 1991 Upton et al., 1992 Massung et al., 1993 Alcami and Smith, 1992 Alcami and Smith, 1996 Alcami and Smith, 1996 Cao et al., 1995 Ahuja and Murphy, 1993 Neote et al., 1993

MIP1 arrantes ŽNeote et al., 1993.. What is the role of the viral chemokine receptor homologue such as EBI1, HVS74 and US28? It is most likely that the homologues act as decoy receptors to bind to host chemokines and inhibit the inflammatory response. This would result in the delay in the recruitment of T cells and monocytes to the site of infection, viral replication would be enhanced and facilitate the spread of the virus. Because of the non-availability of animal models with many of the human herpesviruses, the role of viral chemokines and their receptor mimics in immunopathogenesis is not well-understood. Homologues of cytokine receptors encoded by poxvirus genes are summarised in Table 2 ŽAlcami and Smith, 1995, 1996.. 4. Inhibition of cytokine release or activity A different mechanism of counteracting the host-elicited cytokines is demonstrated by the cytokine response modifier A Ž crmA. gene from poxvirus. CrmA inhibited the activation of the proform of IL-1 b through inactivation of the IL-1 b converting enzyme ŽRay et al., 1992. resulting in inhibition of inflammation. Cowpox virus that lacks this serpin-like protein induces greater inflammatory response and fewer virus particles compared to the virus that includes the inhibitor. Several proteins encoded by human adenoviruses interfere in the actions of cytokines, e.g. by enhancing the resistance to the cytotoxic action of TNF, countering the action of IL-6 and IFN Žreviewed by Hayder and Mullbacher, 1996.. These would result in the facilitation of viral protein synthesis and growth of the virus in the infected cells. 5. Alterations of transcriptional activation of cytokine gene expression by viral proteins 5.1. Expression of Ikb homologue A novel mechanism of immune evasion was recently described for the African Swine fever virus ŽASFV.. The ASFV gene product, A238L was found to be a homologue of

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I kb . Dissociation of I kb from cytosolic NFkb is required before NFkb is translocated to the nucleus where it can act as a transcriptional factor. The transcriptional activation of pro-inflammatory cytokines such as TNF and IL-8 has been shown to be stimulated by the binding of the transcription factor NFkb . A238L was found to inhibit NFkb binding to the NFkb enhancer site of the promoter of the pro-inflammatory cytokine, IL-8 ŽPowell et al., 1996.. Thus, inhibition of transcriptional activation of pro-inflammatory cytokines produced by macrophages may be a mechanism to avoid the host inflammatory response besides producing cytokine or cytokine receptor mimics. 5.2. Decreased actiÕity or leÕel of STATs Infection with viruses have been reported to alter the expression of some cytokines. The exact nature of the hepatitis B viral proteins responsible for modulating cytokine expression is unclear. Twu and Schloemer Ž1989. showed that hepatitis B virus ŽHBV. can suppress IFN-b expression at the transcriptional level and it was later reported that the HBV protein responsible was the core antigen which is the major protein of the nucleocapsid structure ŽWhitten et al., 1991.. This could be one mechanism to explain the lower production of interferon in the serum of chronic hepatitis B carriers resulting in lower antiviral activity. How does HBV interfere with signal transduction? A general first step in cytokine signaling processes is the ligand induced dimerisation of receptor components whose cytoplasmic regions interact to initiate cascades of events. These events activation of tyrosine kinases such as JAK1, 2 or 3. The story is now emerging that JAKs are activated when ligand binds to the receptor, the cytoplasmic domain of some cytokine receptors are phosphorylated and further events occur that result in the phosphorylation of STATs. The activated STATs translocate to the nucleus, bind to specific DNA elements and activate the transcription of nearby genes. One report suggested that the terminal protein of hepatitis B virus can decrease the activity of STATs and this could lead to the inhibition of IFN-a and b signaling ŽFoster et al., 1991.. Adenovirus EIA oncogene has also been reported to reduce the levels of STATs ŽSen and Lengyel, 1992.. Resistance to IFN therapy was associated with the expression of the terminal protein ŽFoster et al., 1993.. Thus, analysis of inhibitory effects of viral proteins on the response to and production of cytokines may lead to therapeutic approaches by which non-reponsiveness to drug treatment may be overcome.

6. Interference of signal transduction Another way where possible cell signaling pathway could be altered is by binding of a viral protein to the cytokine receptor or other signal transducing molecules has been described for hepatitis C and Epstein–Barr virus. 6.1. Binding of a hepatitis C core protein to the lymphotoxin-b receptor To understand the mechanism of Hepatitis C virus persistence, Lai et al. Ž1995. used a yeast two-hybrid system to examine whether HCV proteins interact with cellular

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proteins and thus interfere with host defense mechanism. They found was that HCV core protein interacted with the lymphotoxin ŽLT. receptor, a member of the TNF receptor family. This interaction suggest that HCV core protein can interfere with signal transduction of lymphotoxin receptor and may interfere with the response of HCV-infected cells to the ligands of the TNFR such as TNF, LT-a and CD40L which are important components of cellular defense mechanisms. These interactions can possibly explain the high frequency of HCV persistence and pathogenesis. 6.2. Interaction between latent membrane protein-1 (LMP1) of EBV and TRAF homologue (LAP-1) Using the yeast two-hybrid system, a protein named LAP-1 was found to interact with the EBV latent membrane protein, LMP1 ŽMosialos et al., 1995.. The carboxyl terminus of LAP-1 Žamino acids 302–568. has 45% colinear amino acid identity to TNFR-associated factor 2 ŽTRAF2. which is implicated in growth signalling from the TNF receptor type II. The ability of EBV LMP1 to interact with the TRAF homologue, LAP-1 suggest that LMP-1 could mediate cell transformation and enhance growth promoting signals via the TNF receptor signal transduction pathway. Lymphotoxin has been reported to be an autocrine growth factor for EBV-transformed cell lines ŽEstrov et al., 1993..

7. Immune evasive mechanisms of parasites Immune evasive mechanisms for parasites have been less extensively studied Žreviewed by Riffkin et al., 1996.. Some examples include inhibition of TNF-a expression in cultured macrophage cell line by a protein secreted by Brucella spp. ŽCaron et al., 1996., the induction of TGF-b by Leishmania brasiliensis, detection of an IL-5 like factor in excretory–secretory fluid of Fasciola hepatica ŽMilbourne and Howell, 1990. and a 11 kDa secretory product from Trichostrongylus colubriformis with 32% homology to a IFN a r b induced protein ŽDopheide et al., 1991. and also C–C chemokine homolog encoded by antisense cDNA of a filarial nematode Onchocerca ÕolÕulus ŽErttmann et al., 1995. ŽTable 1.. The IL-5 factor found in the excretory–secretory fluid of Fasciola hepatica, a liver fluke that infects mainly sheep and cattle was shown to stimulate the differentiation and maturation of sheep bone marrow eosinophils in vitro.

8. Conclusion There are a number of immune evasive strategies adopted by pathogens. In the case of viruses, the mechanisms that they use to perpetuate within the host appear reflected in the varied immune modulators known to be encoded in their viral genomes. Such modulation include the antagonism of immune function through the use of soluble versions of cytokine receptors, expression of viral proteins that can interact with cytokine signal transducers, expression of cytokine mimics and induction of host factors

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that can influence the development of Type I or II cytokine responses. In many cases, these strategies have focused on inhibition of local and immediately damaging inflammation. The induction of an inflammatory response is the first line of defense against infectious agents and is rapidly initiated. Cytokine and cytokine receptor mimics clearly function to protect the host from the deleterious effects of the pathogen-induced inflammatory response as well as downregulate the Type I cytokine response, e.g. by altering cytotoxic and natural killer response. Many of the mimics described are either chemokine or chemokine receptor homologues. Recent findings suggest that chemokines appear to have an important role in the regulation of Th differentiation and expansion ŽRutledge et al., 1995; Chensue et al., 1996. rather than just having chemoattractant properties. This is consistent with the possible role of chemokine and their receptor homologues in regulation of the current paradigm Type I or II cytokine responses to evade the immunesurveillance system.

References Ahuja, S.K., Murphy, P.M., 1993. Molecular piracy of mammalian interleukin-8 receptor type B by herpesvirus saimiri. J. Biol. Chem. 268, 20691–20694. Alcami and Smith, 1992. Alcami, A., Smith, G.L., 1995. Cytokine receptors encoded by poxviruses: a lesson in cytokine biology. Immunol. Today 16, 474–478. Alcami, A., Smith, G.L., 1996. Receptors for g-interferon encoded by poxviruses: implications for the unknown origin of vaccinia virus. Trends Microbiol. 4, 321–326. Birkenbach, M., Josefsen, K., Yalamanchill, R., Lenoir, G., Kieff, E., 1993. Epstein–Barr virus-induced genes: first lymphocyte specific G protein-coupled peptide receptors. J. Virol. 67, 2209–2220. Cao, J.X., Gershon, P.D., Black, D.N., 1995. Sequence analysis of HindIII Q2 fragment of capripox virus reveals a putative gene encoding a G protein-coupled chemokine receptor homologue. Virology 209, 207–212. Caron, E., Gross, A., Liautard, J.-P., Dornand, J., 1996. Brucella species release a specific, protease-sensitive inhibitor of TNF-a expression, active on human macrophage-like cells. J. Immunol. 156, 2885–2893. Chensue, S.W., Warmington, K.S., Ruth, J.H., Sanghi, P.S., Lincoln, P., Kunkel, S., 1996. Role of monocyte chemoattractant protein-1 ŽMCP-1. in Th1 Žmycobacterial. and Th2 Žschistosomal. antigen-induced granuloma formation. J. Immunol. 157, 14602–14608. Davis-Poynter, N.J., Farrell, H.E., 1996. Masters of deception: a review of herpesvirus immune evasion strategies. Immunol. Cell Biol. 74, 513–522. De Waal Malefyt, Yssel, H., Roncarolo, M.-G., Spits, H., de Vries, J.E., 1992. Interleukin-10. Curr. Opin. Immunol. 4, 314–320. Devergne, O., Hummel, M., Koeppen, H., Le Beau, M.M., Nathanson, E.C., Kieff, E., Birkenbach, M., 1996. A novel interleukin-12 p40 related protein induced by latent Epstein–Barr virus infection in B lymphocytes. J. Virol. 70, 1143–1153. Dopheide, T.A., Tachedjian, M., Phillips, C., Frenkel, M.J., Wagland, B.M., Ward, C.W., 1991. Molecular characterisation of a protective 11 kDa excretory–secretory protein from the parasitic stages of Trichostrongylus colubriformis. Mol. Biochem. Parasitol. 45, 101–108. Erttmann, K.D., Buttner, D.W., Gallin, M.Y., 1995. A putative protein related to human chemokines encoded antisense to the cDNA of an Onchocerca ÕolÕulus antigen. Trop. Med. Parasitol. 46, 123–130. Estrov, Z., Kurzrock, R., Pocsik, E., Pathak, S., Kantarjian, H.M., Zipf, T.F., Harris, D., Talpaz, M., Aggarwal, B.B., 1993. Lymphotoxin is an autocrine growth factor for Epstein–Barr virus-infected B cell lines. J. Exp. Med. 177, 763–774. Gompels, U.A., Nicholas, J., Lawrence, G., Jones, M., Thomson, B.J., Martin, M.E.D., Efstathiou, S.,

H.-F. Seowr Veterinary Immunology and Immunopathology 63 (1998) 139–148

147

Craxton, M., Macaulay, H.A., 1995. The DNA sequence of human herpesvirus-6-structure, coding content and genome evolution. Virology 209, 29–51. Haig, D.M., 1996. Poxvirus interference with the host cytokine response. J. Interferon Cytokine Res. 16, 653. Hayder, H., Mullbacher, A., 1996. Molecular basis of immune evasion strategies by adenoviruses. Immunol. Cell Biol. 74, 504–512. Hsu, D.-H., de Waal, R., Fiorentino, D.F., Dang, M.-N., Vieira, P., deVries, J., Spits, H., Mosmann, T.R., Moore, K.W., 1990. Expression of interleukin-10 activity by Epstein–Barr virus protein BCRF1. Science 250, 830–832. Foster, G.R., Ackrill, M.A., Goldin, R.D., Kerr, I.M., Thomas, H.C., Stark, G.R., 1991. Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons a and g and double-stranded RNA. Proc. Acad. Natl. Sci. USA. 88, 2888–2892. Foster, G., Goldin, R.D., Hay, A., McGarvey, M.J., Stark, G., Thomas, H.C., 1993. Expression of the terminal protein of hepatitis B virus is associated with failure to respond to interferon therapy. Hepatology 17, 757–762. Lai, M.M., Matsumoto, M., Zhu, N., Hwang, S.B., Lo, S.-Y., Ou, J., van Arsdale, T., Ware, C.F., 1995. Mechanism of hepatitis C virus persistence and pathogenesis: interactions between the viral core protein and members of tumor necrosis factor receptor family. IV International Symposium on RNA positive strand virus, May 25–30, 1995, Jaarbeus Congress Centre, Utrecht, Netherlands, abstract PS6-03. Lotz, M., Tsoukas, C.D., Fong, S., Fong, L., Carson, D.A., Vaughan, J.H., 1985. Regulation of Epstein–Barr virus infection by recombinant interferons. Selected sensitivity to interferon-g . Eur. J. Immunol. 15, 520–525. Massung, R.F., Jayarama, V., Moyer, R.W., 1993. DNA sequence analysis of conserved and unique region of swinepox virus: identification of genetic elements supporting phenotypic observations including a novel G protein-coupled receptor homologue. Virology 197, 511–528. Milbourne, E.A., Howell, M.J., 1990. Eosinophil responses to Fasciola hepatica in rodents. Int. J. Parasitol. 20, 705–708. Miyazaki, I., Cheung, R.K., Dosch, H.M., 1993. Viral interleukin-10 is critical for the induction of B cell growth transformation by Epstein–Barr virus. J. Exp. Med. 178, 439–447. Moore, K.W., Viera, P., Fiorentino, D.F., Trounstine, M.L., Khan, T.A., Mosmann, T.R., 1990. Homology of cytokine synthesis inhibitory factor ŽIL-10. to the Epstein–Barr virus gene BCRFI. Science 248, 1230–1233. Moore, P.S., Boshoff, C., Weiss, R.A., Chang, Y., 1996. Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science 274, 1739–1744. Mosialos, G., Birkenbach, M., Yalamanchili, R., van Arsdale, T., Ware, C., Kieff, E., 1995. The Epstein–Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80, 389–399. Neote et al., 1993. Nicholas, J., Cameron, K.R., Honess, R.W., 1992. Herpesvirus saimiri encodes homologues of G protein-coupled receptors and cyclins. Nature 355, 362–365. Powell, P.P., Dixon, L.K., Parkhouse, R.M.E., 1996. An I kb homologue encoded by African swine fever virus provides a novel mechanism for downregulation of pro-inflammatory cytokine responses in host macrophages. J. Virol. 70, 8527–8533. Ray, C.A., Black, R.A., Kronheim, S.R., Greenstreet, T.A., Sleath, P.R., Salvesen, G.S., Pickup, D.J., 1992. Viral inflammation of inflammation: cowpox virus encodes an inhibitor of the interleukin-1 b converting enzyme. Cell 69, 597–604. Riffkin, M., Seow, H.-F., Jackson, D., Brown, L., Wood, P., 1996. Defense against the immune barragehelminth survival strategies. Immunol. Cell Biol. 74, 564–574. Rode, H.J., Janssen, W., Rosen-Walff, A., Bugert, J.J., Thein, P., Becker, Y., Darai, G., 1993. The genome of equine herpesvirus type 2 harbors an interleukin-10 ŽIL-10.-like gene. Virus Genes 7, 111–116. Rouvier, E., Luciani, M.F., Mattei, M.G., Denizot, F., Golstein, P., 1993. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J. Immunol. 150, 5445–5456. Rutledge, B.J., Rayburn, H., Rosenberg, R., North, R.J., Gladue, R.P., Corless, C.L., Rollins, B.J., 1995. High levels of monocyte chemoattractant protein-1 expression in transgenic mice increases their susceptibility to intracellular pathogens. J. Immunol. 155, 4838–4843.

148

H.-F. Seowr Veterinary Immunology and Immunopathology 63 (1998) 139–148

Schang, L.M., Hossain, A., Jones, C., 1996. A latency-related gene of bovine herpesvirus which encodes a product which inhibits cell cycle progression. J. Virol. 70, 3807–3814. Sen, G.C., Lengyel, P., 1992. The interferon system. A bird’s eye view of its biochemistry. J. Biol. Chem. 267, 5017–5020. Senkevich, T.G., Bugert, J.J., Sisler, J.R., Koonin, E.V., Darai, G., Moss, B., 1996. Genome sequence of a human tumorigenic poxvirus-prediction of specific host response-evasion genes. Science 273, 813–816. Smith, C.A., Davis, T., Wignall, J.M., Din, W.S., Farrah, T., Upton, C., McFadden, G., Goodwin, R.G., 1991. T2 open reading rame from the shope fibroma virus encodes a soluble form of the TNF receptor. Biochem. Biophys. Res. Commun. 176, 335–342. Spriggs, M.K., 1996. One step ahead of the game: viral immunomodulatory molecules. Ann. Rev. Immunol. 14, 101–130. Swaminathan, S., Hesselton, R., Sullivan, J., Kieff, E., 1993. Epstein–Barr virus recombinants with specifically mutated BCRF1 genes. J. Virol. 67, 7406–7413. Thorley-Lawson, D.A., 1981. The transformation of adult but not newborn human lymphocytes by Epstein–Barr virus and phytohemagglutinin is inhibited by interferon: the early suppression by T cells of Epstein–Barr virus infection is mediated by interferon. J. Immunol. 126, 829–833. Twu, J.S., Schloemer, R.H., 1989. Transcription of the human beta interferon gene is inhibited by hepatitis B virus. J. Virol. 63, 3065–3071. Upton, C., Macen, K.L., Schreiber, M., McFadden, G., 1991. Myxoma virus expresses a secreted protein with homology to the tumor necrosis factor receptor gene family that contributes to viral virulence. Virology 184, 370–382. Upton, C., Mossman, K., McFadden, G., 1992. Encoding of a homologue of the IFN-g receptor by myxoma virus. Science 258, 1369–1372. Whitten, T.M., Quets, A.T., Schloemer, R.H., 1991. Identification of the Hepatitis B virus factor that inhibits expression of the beta interferon gene. J. Virol. 65, 4699–4704. Yao, Z., Fanslow, W.C., Seldin, M.F., Rousseau, A.-M., Painter, S., Comeau, M.R., Cohen, J.I., Spriggs, M.K., 1995. Herpesvirus saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3, 811–821.