{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:53:01Z","timestamp":1789433581110,"version":"build-2803163510"},"reference-count":91,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T00:00:00Z","timestamp":1603843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01-AA025854"],"award-info":[{"award-number":["R01-AA025854"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01-AI020211"],"award-info":[{"award-number":["R01-AI020211"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21 AI142507"],"award-info":[{"award-number":["R21 AI142507"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Cytomegaloviruses all encode the viral inhibitor of caspase-8-induced apoptosis (vICA). After binding to this initiator caspase, vICA blocks caspase-8 proteolytic activity and ability to activate caspase-3 and\/or caspase-7. In this manner, vICA has long been known to prevent apoptosis triggered via tumor necrosis factor (TNF) family death receptor-dependent extrinsic signaling. Here, we employ fully wild-type murine cytomegalovirus (MCMV) and vICA-deficient MCMV (\u2206M36) to investigate the contribution of TNF signaling to apoptosis during infection of different cell types. \u2206M36 shows the expected ability to kill mouse splenic hematopoietic cells, bone marrow-derived macrophages (BMDM), and dendritic cells (BMDC). Antibody blockade or genetic elimination of TNF protects myeloid cells from death, and caspase-8 activation accompanies cell death. Interferons, necroptosis, and pyroptotic gasdermin D (GSDMD) do not contribute to myeloid cell death. Human and murine fibroblasts or murine endothelial cells (SVEC4-10) normally insensitive to TNF become sensitized to \u2206M36-induced apoptosis when treated with TNF or TNF-containing BMDM-conditioned medium. We demonstrate that myeloid cells are the natural source of TNF that triggers apoptosis in either myeloid (autocrine) or non-myeloid cells (paracrine) during \u2206M36 infection of mice. Caspase-8 suppression by vICA emerges as key to subverting innate immune elimination of a wide variety of infected cell types.<\/jats:p>","DOI":"10.3390\/v12111221","type":"journal-article","created":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T11:43:06Z","timestamp":1603885386000},"page":"1221","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["TNF Signaling Dictates Myeloid and Non-Myeloid Cell Crosstalk to Execute MCMV-Induced Extrinsic Apoptosis"],"prefix":"10.3390","volume":"12","author":[{"given":"Pratyusha","family":"Mandal","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Louise","family":"McCormick","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceuticals, Novato, CA 94949, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward S.","family":"Mocarski","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1002\/cbin.11137","article-title":"Cell death: A review of the major forms of apoptosis, necrosis and autophagy","volume":"43","year":"2019","journal-title":"Cell Biol. 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