Variation in Ligand Binding Specificities of a Novel Class of Poxvirus-encoded Tumor Necrosis Factor-binding Protein

The Yatapoxviruses encode a distinct class of secreted TNF-binding protein (TNF-BP) that resembles an MHC class I heavy chain but distinct from any other known TNF inhibitor. Characterization of these viral TNF inhibitors from Tanapox virus, Yaba monkey tumor virus (YMTV) and a closely related version from Swinepox virus revealed dramatically differential TNF binding specificities for different mammalian species. The Tanapox virus 2L protein (TPV-2L) formed inhibitory complexes with human TNF, and interacted with monkey and canine TNF with high affinity but rabbit TNF with low affinity. On the other hand, YMTV-2L bound human and monkey TNF with high affinity but rabbit TNF with only low affinity. The TNF-BP from swinepox virus (SPV003/148) only interacted with porcine TNF with high affinity. The observed TNF binding analysis mirrored the biological activity of these TNF-binding protein to block TNF-induced cellular cytolysis. TPV-2L and YMTV-2L also inhibited the human TNF-mediated signaling in cells but TPV-2L exhibited higher affinity for human TNF (KD, 43 pm) compared with monkey (KD, 120 pm) whereas for YMTV-2L, the affinities were reversed (human TNF KD, 440 pm; monkey TNF KD, 230 pm). The interaction domain of human TNF with TNF-binding proteins is significantly different from that of TNFRs, as determined using human TNF mutants. We conclude that these poxvirus TNF-binding proteins represent a new class of TNF inhibitors and are distinct from the viral TNF receptor homologues characterized to date. The Yatapoxviruses encode a distinct class of secreted TNF-binding protein (TNF-BP) that resembles an MHC class I heavy chain but distinct from any other known TNF inhibitor. Characterization of these viral TNF inhibitors from Tanapox virus, Yaba monkey tumor virus (YMTV) and a closely related version from Swinepox virus revealed dramatically differential TNF binding specificities for different mammalian species. The Tanapox virus 2L protein (TPV-2L) formed inhibitory complexes with human TNF, and interacted with monkey and canine TNF with high affinity but rabbit TNF with low affinity. On the other hand, YMTV-2L bound human and monkey TNF with high affinity but rabbit TNF with only low affinity. The TNF-BP from swinepox virus (SPV003/148) only interacted with porcine TNF with high affinity. The observed TNF binding analysis mirrored the biological activity of these TNF-binding protein to block TNF-induced cellular cytolysis. TPV-2L and YMTV-2L also inhibited the human TNF-mediated signaling in cells but TPV-2L exhibited higher affinity for human TNF (KD, 43 pm) compared with monkey (KD, 120 pm) whereas for YMTV-2L, the affinities were reversed (human TNF KD, 440 pm; monkey TNF KD, 230 pm). The interaction domain of human TNF with TNF-binding proteins is significantly different from that of TNFRs, as determined using human TNF mutants. We conclude that these poxvirus TNF-binding proteins represent a new class of TNF inhibitors and are distinct from the viral TNF receptor homologues characterized to date. The complex and ever evolving interactions between host and pathogens has led to an evolutionary interplay between the host immune system and countermeasures by the pathogens. Large DNA viruses such as poxviruses, which replicate exclusively within the cytoplasm of infected cells, encode diverse immunomodulatory proteins to modulate, avoid, or diminish multiple antiviral responses mediated by hosts (1Seet B.T. Johnston J.B. Brunetti C.R. Barrett J.W. Everett H. Cameron C. Sypula J. Nazarian S.H. Lucas A. McFadden G. Annu. Rev. Immunol. 2003; 21: 377-423Crossref PubMed Scopus (493) Google Scholar, 2Alcami A. Nat. Rev. Immunol. 2003; 3: 36-50Crossref PubMed Scopus (448) Google Scholar, 3Nazarian S. McFadden G. Future Virol. 2006; 1: 123-132Crossref Google Scholar). Tumor necrosis factor (TNF), 2The abbreviations used are: TNF, tumor necrosis factor; TNF-BP, TNF-binding protein; vTNF-BP, viral TNF-BP; TPV, Tanapox virus; YMTV, Yaba monkey tumor virus; SPV, swinepox virus; YLDV, Yaba-like disease virus; TNFR, TNF receptor; LTα, lymphotoxin-α; Crm, cytokine response modifier; CRD, cysteine-rich domain; DPV, deerpox virus; SPR, surface plasmon resonance; NTA, nitrilotriacetic acid; hTNF, human TNF; ORF, open reading frame. secreted primarily by macrophages and monocytes, is a potent mediator cytokine of inflammation and the immune response to various pathogens (4Aggarwal B.B. Nat. Rev. Immunol. 2003; 3: 745-756Crossref PubMed Scopus (2153) Google Scholar, 5Ware C.F. Annu. Rev. Immunol. 2005; 23: 787-819Crossref PubMed Scopus (370) Google Scholar). TNFα, the prototype member of the TNF superfamily, forms trimers and is expressed as both a membrane-bound 26-kDa and a soluble 17-kDa form, both of which are biologically active. The biological effects of TNFα (here called TNF) are mediated by binding to two receptors, TNFR1 (p55/p60) or TNFR2 (p75/80), members of the TNFR superfamily of proteins (6Mocellin S. Rossi C.R. Pilati P. Nitti D. Cytokine Growth Factor Rev. 2005; 16: 35-53Crossref PubMed Scopus (256) Google Scholar, 7Hehlgans T. Pfeffer K. Immunology. 2005; 115: 1-20Crossref PubMed Scopus (625) Google Scholar). TNF is also directly involved in the pathogenesis of inflammatory and autoimmune diseases such as rheumatoid arthritis, septic shock, Crohn disease and other syndromes (6Mocellin S. Rossi C.R. Pilati P. Nitti D. Cytokine Growth Factor Rev. 2005; 16: 35-53Crossref PubMed Scopus (256) Google Scholar). The broad inhibitory effects of TNF have forced many viruses to acquire specific strategies to neutralize TNF or TNF-mediated responses. Of particular interest are poxvirus-encoded molecules that bind and sequester extracellular TNF prior to TNFR engagement (8Cunnion K.M. Mol. Genet. Metab. 1999; 67: 278-282Crossref PubMed Scopus (40) Google Scholar, 9Benedict C.A. Cytokine Growth Factor Rev. 2003; 14: 349-357Crossref PubMed Scopus (61) Google Scholar, 10Rahman M. McFadden G. PLoS Pathogens. 2006; 2: 66-77Crossref Scopus (155) Google Scholar). Two classes of viral-encoded anti-TNF proteins have been described: secreted homologues of TNFRs and secreted proteins that bind TNF, termed vTNFRs and vTNF-BP, respectively. Among the poxvirus-encoded vTNFRs, two major categories have been described: the T2-like inhibitors encoded by leporipoxviruses and the cytokine response modifier (Crm)-like orthologs encoded by orthopoxviruses (8Cunnion K.M. Mol. Genet. Metab. 1999; 67: 278-282Crossref PubMed Scopus (40) Google Scholar). The first identified such immunomodifier targeted to TNF was the T2 TNFR homolog in Shope Fibroma virus (SFV), a leporipoxvirus, which causes tumors in rabbits (11Schreiber M. Rajarathnam K. McFadden G. J. Biol. Chem. 1996; 271: 13333-13341Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 12Schreiber M. McFadden G. Virology. 1994; 204: 692-705Crossref PubMed Scopus (57) Google Scholar). The function of such a soluble viral receptor mimic is to bind and sequester host-elicited TNF and LTα, thereby preventing activation of cellular TNF receptors and TNF-mediated responses that lead to downstream antiviral effects. The closely related myxoma virus encoded M-T2 is an early glycosylated, dimeric, secreted protein that specifically binds to, and inhibits rabbit TNF (11Schreiber M. Rajarathnam K. McFadden G. J. Biol. Chem. 1996; 271: 13333-13341Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 12Schreiber M. McFadden G. Virology. 1994; 204: 692-705Crossref PubMed Scopus (57) Google Scholar). Additionally, the M-T2 protein is also able to inhibit apoptosis in virus-infected lymphocytes (13Schreiber M. Sedger L. McFadden G. J. 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A. 1998; 95: 3786-3791Crossref PubMed Scopus (110) Google Scholar, 18Saraiva M. Alcami A. J. Virol. 2001; 75: 226-233Crossref PubMed Scopus (96) Google Scholar), Ectromelia virus encodes only CrmD (19Smith V.P. Bryant N.A. Alcamí A. J. Gen. Virol. 2000; 81: 1223-1230Crossref PubMed Scopus (154) Google Scholar) and variola (VaV) and monkeypox virus, which causes smallpox-like disease in humans, encode CrmB only. Although all of the above vTNFRs possess the conserved TNF binding cysteine-rich domains (CRDs), CrmC and CrmE lack the 150-residue C-terminal domain present in CrmB and CrmD. Recently, it has been demonstrated that the VaV-encoded CrmB also binds to chemokines in addition to TNF (20Alejo A. Ruiz-Arguello M.B. Ho Y. Smith V.P. Saraiva M. Alcami A. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 5995-6000Crossref PubMed Scopus (119) Google Scholar). The TNF binding CRD-containing domain remains solely in the N-terminal region of CrmB, whereas the C-terminal domain that binds chemokines represents a newly identified family of poxvirus chemokine inhibitors (20Alejo A. Ruiz-Arguello M.B. Ho Y. Smith V.P. Saraiva M. Alcami A. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 5995-6000Crossref PubMed Scopus (119) Google Scholar). Among the vaccinia virus (VV) strains, Lister, USSR, and Evans encode CrmC and CrmE; however other strains such as Western Reserve, Copenhagen, DryVax (Wyeth), and Tian-Tan encode truncated vTNFRs that are not functional (21Alcamí A. Khanna A. Paul N.L. Smith G.L. J. Gen. Virol. 1999; 80: 949-959Crossref PubMed Scopus (105) Google Scholar). Cowpox and mousepox virus also encode an ortholog of TNFR family that binds and inhibits J.F. Smith C.A. Ray C.A. Smith T.D. Pickup D.J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus (57) Google Scholar, M. Smith P. Alcami A. J. PubMed Scopus Google Scholar). 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The of interest were by with specific and viral DNA as were or and the proteins were expressed to the C-terminal and The of all DNA was by DNA of TPV-2L and of TPV-2L has been described C.R. M. J. Barrett J.W. A. P. K. McFadden G. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus (57) Google Scholar). of the YMTV-2L 2L of the to the TPV-2L was by using the and the The was to of the of the to the TPV-2L was by using the and the The was to The YMTV-2L and from and were and to as and were by using the system the were a the were and cells, and the were from the viruses were in to a higher virus for protein cells were infected of infection of with the were by for and high for and using a were and was by affinity the The protein was using and by to a protein and were The was by Western and protein was by with The protein was by the or and TNF-mediated for cells and porcine TNF-mediated for porcine cells was by using a C.A. Hu F.-Q. Smith T.D. Richards C.L. Smolak P. Goodwin R.G. Pickup D.J. Virology. 1996; 223: 132-147Crossref PubMed Scopus (103) Google Scholar). cells were in in a of of with and was and TNF for and TNF, for canine TNF, and for porcine TNF) with in the or of of inhibitors were The of all these in of cells were with and for with of in were with and the was with and the was were in of was by Cytokine binding and affinity were by using a of was using the The surface was with in by of the protein by of protein a of the the various were a of for The surface was by from the surface by of analysis the proteins were low of using of the cytokine were a of a of and to for an by the to The surface was using or were by the responses and the response of a was from all to The were with the by using a TNF-mediated was in TNF that was with different of inhibitors for in with The was to cells in with for were and for Western as described C.R. M. J. Barrett J.W. A. P. K. McFadden G. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus (57) Google Scholar). of of protein from was by of the of the was used to TNF-induced activation in TNF-mediated cells were for with human TNF or or TNF with of TPV-2L or The cells were and to was determined using and a with of TPV-2L encodes a high affinity human TNF-binding protein C.R. M. J. Barrett J.W. A. P. K. McFadden G. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus (57) Google Scholar). The of protein are present in other members of the the member of the and the deerpox virus C.L. G. A. L. J. Virol. 2005; PubMed Scopus Google Scholar). these newly identified class of poxvirus-encoded MHC class TNF-binding TPV-2L is to and YMTV-2L and to and and between and the 2L family of have and expressed YMTV-2L, and as proteins using the system the proteins were secreted from cells and have of and of poxvirus MHC class in a new of the evolutionary host of the viruses is the to and the of in multiple that other mammalian that the 2L family of proteins bind to TNF from other species. using have demonstrated that TPV-2L expressed using bound to human TNF with high affinity (KD, 43 however it not bind to or TNF and other members of TNF superfamily of proteins C.R. M. J. Barrett J.W. A. P. K. McFadden G. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus (57) Google Scholar). for TNF from different and other YMTV-2L, and high TNF and were the and protein surface The that were were using in addition to human TNF, also bound to and rabbit TNF The YMTV-2L bound to and rabbit TNF but not to or TNF with other LTα, or The the other bound to only porcine TNF with high affinity and of the TPV-2L with the affinity of the TPV-2L family of proteins with TNF, binding analysis of various of The proteins were low of and of TNF an of 120 was to the of the binding of YMTV-2L, and to various of TPV-2L bound with high affinity to TNF from monkey (KD, 120 pm) and KD, pm) and with affinity to rabbit TNF (KD, Although observed TPV-2L bound to porcine TNF high the interaction was not analysis demonstrated that human TNF a TNF from other the of and canine TNF are all The of human TNF was also and monkey and canine TNF, respectively. rabbit TNF demonstrated and affinity with a of binding and affinity of to various in a new analysis using a demonstrated that YMTV-2L bound with high affinity to both human (KD, 440 pm) and monkey TNF (KD, 230 pm) but the affinity for monkey TNF was higher for human TNF is monkey TNF has a and human compared with YMTV-2L has a with human TNF that in a higher TNF also bound to YMTV-2L with affinity of TNF bound to YMTV-2L high but the interaction was not the affinity of porcine TNF with the protein was a and of porcine TNF were TNF bound with high affinity to with a of TNF bound with a and a which is to binding of human and monkey TNF with of TNF-mediated by TPV-2L of TNF-mediated biological activity by YMTV-2L, and was by using and rabbit TNF) cells and porcine cells porcine addition to human TNF, TPV-2L was also able to inhibit the by monkey and canine TNF but not by rabbit or porcine TNF The of TPV-2L to neutralize human and monkey TNF was whereas for canine TNF it was higher neutralize human and monkey TNF of TPV-2L was whereas in the of canine TNF pm) of the protein was The of TNF-mediated by TPV-2L family members closely interaction YMTV-2L was able to inhibit the by human and monkey TNF but not by rabbit or canine TNF The of YMTV-2L to neutralize human TNF was higher the monkey TNF the affinity for monkey TNF, as observed with neutralize human TNF of YMTV-2L was for monkey TNF pm) it was of the YMTV-2L has inhibitory activity TPV-2L with human and monkey inhibit the biological activity of porcine TNF, the was using porcine cells was able to inhibit the by porcine TNF but not by TNF from other species. The of to neutralize porcine TNF was which is to porcine TNF pm) of TNF-mediated two major signaling downstream of TNF receptors, of or activation G. PubMed Scopus Google Scholar). We the of these TNF-binding proteins to as inhibitors by to block TNF activity in We TNF with of We of the of or activation by these addition to TPV-2L and YMTV-2L exhibited for TNF-mediated of in cells The of TPV-2L and YMTV-2L was and respectively. were also able to inhibit TNF but not activation and not of TNF with TPV-2L and TNF with TNFR1 and TNFR2 with different affinity to biological using binding analysis demonstrated that human TNF has significantly higher affinity for TNFR1 TNFR2 M. H. G. P. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: PubMed Scopus Google Scholar). in human TNF have identified for binding to or both TNF in or the and which the between two the of the are H. D. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, P. J. J. 1994; PubMed Scopus Google Scholar). bound only to whereas bound only to TNFR2 H. D. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, P. J. J. 1994; PubMed Scopus Google Scholar). We have these two human TNF for to bind and compared affinity with soluble human TNFR1 and TNFR2 using binding analysis of human TNF with soluble TNFR1 and TNFR2 using that human TNF has higher affinity to TNFR1 (KD, pm) TNFR2 (KD, pm) and TNF bound to soluble TNFR1 with reduced affinity (KD, pm) but not bind to TNFR2 higher On the other hand, bound only to soluble TNFR2 with reduced affinity of (KD, TNF but not bind to TNFR1 all and binding and affinity of TNFR1 and TNFR2 to human TNF and in a new the TNF bound to TPV-2L with different binding as determined by using and The exhibited reduced binding by of compared with demonstrated only a compared with that of these are in of binding to compared with the effects TNFR1 or not any binding to YMTV-2L, whereas exhibited reduced binding by compared with and that and are as for interaction with YMTV-2L as are for but not in of binding with the human TNF, both the human were to bind to not TNF is a mediator in host and immune response various viruses M. McFadden G. PLoS Pathogens. 2006; 2: 66-77Crossref Scopus (155) Google Scholar). it is not that viruses acquire strategies to the TNF response (8Cunnion K.M. Mol. Genet. Metab. 1999; 67: 278-282Crossref PubMed Scopus (40) Google Scholar, 9Benedict C.A. Cytokine Growth Factor Rev. 2003; 14: 349-357Crossref PubMed Scopus (61) Google Scholar). The of a new class of TNF-binding protein C.R. M. J. Barrett J.W. A. P. K. McFadden G. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus (57) Google Scholar) the and of viral countermeasures to TNF different Among the poxvirus homologues of the 2L family of TNF-BP are present only in members of the swinepox virus, and deerpox analysis of that these viruses a distinct poxvirus with the 2L orthologs a by a C. S. P. Smith G.L. J. Gen. Virol. PubMed Scopus Google Scholar). the protein of Although TPV-2L and YMTV-2L for and are only to TPV-2L We have that YMTV-2L, and all TNF binding which are biologically but from Among the TPV-2L the TNF binding as as the of TNF-mediated On the other hand, has a in of both binding affinity and of TNF-mediated that all of the possess thereby to TNF, but specific TNF The in binding to TNF from different by these also to the TNF species. TPV-2L and YMTV-2L bind both human and monkey TNF with high affinity. only rabbit TNF bound to both TPV-2L and YMTV-2L and rabbit TNF are and with human that for binding or of the different and the these as to particular host immune The of the mammalian have diverse inhibitors to inhibit the TNF vTNFRs, the T2-like proteins and Crm family significantly vary in binding to TNF or molecules from different and the of TNF-mediated (1Seet B.T. Johnston J.B. Brunetti C.R. Barrett J.W. Everett H. Cameron C. Sypula J. Nazarian S.H. Lucas A. McFadden G. Annu. Rev. Immunol. 2003; 21: 377-423Crossref PubMed Scopus (493) Google Scholar, A. Ruiz-Arguello M.B. Ho Y. Smith V.P. Saraiva M. Alcami A. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 5995-6000Crossref PubMed Scopus (119) Google Scholar). viral TNF inhibitors also different of to host proteins and The myxoma virus M-T2 protein for binds and inhibits rabbit TNF only M. McFadden G. Virology. 1994; 204: 692-705Crossref PubMed Scopus (57) Google Scholar). Although the Crm family of proteins bind human and TNF with different vary primarily in of TNF-mediated CrmB and and CrmD and both bind and inhibit TNF and (15Hu F.-Q. Smith C.A. Pickup D.J. Virology. 1994; 204: 343-356Crossref PubMed Scopus (162) Google Scholar, 17Loparev V.N. Parsons J.M. Knight J.C. Panus J.F. Ray C.A. Buller R.M.L. Pickup D.J. Esposito J.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3786-3791Crossref PubMed Scopus (110) Google Scholar, A. Ruiz-Arguello M.B. Ho Y. Smith V.P. Saraiva M. Alcami A. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 5995-6000Crossref PubMed Scopus (119) Google Scholar). Although both CrmD and CrmE bind TNF from and only inhibit human TNF-mediated V.N. Parsons J.M. Knight J.C. Panus J.F. Ray C.A. Buller R.M.L. Pickup D.J. Esposito J.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3786-3791Crossref PubMed Scopus (110) Google Scholar, 18Saraiva M. Alcami A. J. Virol. 2001; 75: 226-233Crossref PubMed Scopus (96) Google Scholar). that the of a between binding and The TNF bind to TNFR1 or TNFR2 to biological responses. with human and TNF have identified and for binding with of these receptors J. T. J. 1991; PubMed Scopus (110) Google Scholar, Smith P. J. J. 1994; PubMed Scopus Google Scholar, P. P. P. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The TNF and that the between of any two of the are for have identified that are for binding to of the receptors H. D. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, P. J. J. 1994; PubMed Scopus Google Scholar). between and and to binding of to TNFR2 to a binding to the and the TNF binding activity for TNFR2 but all the binding activity for TNFR1 H. D. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The lack of YMTV-2L binding to TNF that or both of these two are in with YMTV-2L, in a to interaction with TNFR2 and to the of of of with binding to TNFR1 a interaction of TNF surface with TNFR1 H. D. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar). in region binding for TNFR2 but reduced binding activity for affinity binding with both TPV-2L and YMTV-2L, that these are not in binding with of the the binding with human and other TNF and of human TNF-mediated biological TPV-2L is a potent of human TNF YMTV-2L and is On the other hand, YMTV-2L higher affinity for monkey all the members of new class of TNF-binding proteins with the and domains of cellular MHC class I virus a human also encodes a MHC class I homolog that forms a complex with in of infected cells by cells has not been Virology. 1998; PubMed Scopus Google Scholar). The 2L family of MHC class TNF-binding proteins described to encoded MHC class I that these distinct have been The represent a of a class of viral TNF and in interaction with TNF, of the potent Future the to the and of the interaction between and TNF complex the of interaction of TNF and class of We S. Nazarian and for and and D. for with the with

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