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TNF Signaling Dictates Myeloid and Non-Myeloid Cell Crosstalk to Execute MCMV-Induced Extrinsic Apoptosis
| Content Provider | MDPI |
|---|---|
| Author | Mandal, Pratyusha McCormick, A. Mocarski, Edward |
| Copyright Year | 2020 |
| Description | 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 (∆M36) to investigate the contribution of TNF signaling to apoptosis during infection of different cell types. ∆M36 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 ∆M36-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 ∆M36 infection of mice. Caspase-8 suppression by vICA emerges as key to subverting innate immune elimination of a wide variety of infected cell types. |
| Starting Page | 1221 |
| e-ISSN | 19994915 |
| DOI | 10.3390/v12111221 |
| Journal | Viruses |
| Issue Number | 11 |
| Volume Number | 12 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2020-10-28 |
| Access Restriction | Open |
| Subject Keyword | Viruses Virology Apoptosis Extrinsic Apoptosis Intrinsic Apoptosis Pyroptosis Necroptosis Inflammation Tnf Ifn Dna Virus Cytomegalovirus Replication Hcmv Mcmv Ul36 M36 Vica Caspase-8 Myeloid Cells Cell Death |
| Content Type | Text |
| Resource Type | Article |
