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Viral FLIPs (Fas-linked ICE-like protease [FLICE; caspase-8]-like inhibitor proteins) are potent inhibitors of death receptor-induced apoptosis and programmed necrosis. Surprisingly, transgenic expression of the viral FLIP MC159 from molluscum contagiosum virus (MCV) in mice enhanced rather than inhibited the innate immune control of vaccinia virus (VV) replication. This effect of MC159 was specifically manifested in peripheral tissues such as the visceral fat pad, but not in the spleen. VV-infected MC159 transgenic mice mounted an enhanced innate inflammatory reaction characterized by increased expression of the chemokine CCL-2\/MCP-1 and infiltration of \u03b3\u03b4 T cells into peripheral tissues. Radiation chimeras revealed that MC159 expression in the parenchyma, but not in the hematopoietic compartment, is responsible for the enhanced innate inflammatory responses. The increased inflammation in peripheral tissues was not due to resistance of lymphocytes to cell death. Rather, we found that MC159 facilitated Toll-like receptor 4 (TLR4)- and tumor necrosis factor (TNF)-induced NF-\u03baB activation. The increased NF-\u03baB responses were mediated in part through increased binding of RIP1 to TNFRSF1A-associated via death domain (TRADD), two crucial signal adaptors for NF-\u03baB activation. These results show that MC159 is a dual-function immune modulator that regulates host cell death as well as NF-\u03baB responses by innate immune signaling receptors.<\/jats:p>","DOI":"10.1128\/jvi.00983-10","type":"journal-article","created":{"date-parts":[[2010,8,12]],"date-time":"2010-08-12T02:28:22Z","timestamp":1281580102000},"page":"10467-10476","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":28,"title":["Viral Cell Death Inhibitor MC159 Enhances Innate Immunity against Vaccinia Virus Infection"],"prefix":"10.1128","volume":"84","author":[{"given":"Sreerupa","family":"Challa","sequence":"first","affiliation":[{"name":"Department of Pathology"},{"name":"Immunology and Virology Program"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Woelfel","sequence":"additional","affiliation":[{"name":"Department of Pathology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Guildford","sequence":"additional","affiliation":[{"name":"Department of Pathology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Moquin","sequence":"additional","affiliation":[{"name":"Department of Pathology"},{"name":"Immunology and Virology Program"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis Ka-Ming","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pathology"},{"name":"Immunology and Virology Program"},{"name":"Diabetes and Endocrinology Research Center, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02571-09"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.4.2429"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1102-1013"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.4.1172"},{"key":"e_1_3_2_6_2","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.4049\/jimmunol.131.3.1531","volume":"131","year":"1983","unstructured":"Bukowski, J. 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