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Treatment options for chronic infection are limited, and the development of novel therapeutic strategies requires a greater understanding of how\n                      <jats:italic>C. burnetii<\/jats:italic>\n                      interacts with immune signaling. Cell death responses are known to be manipulated by\n                      <jats:italic>C. burnetii<\/jats:italic>\n                      , but the role of caspase-8, a central regulator of multiple cell death pathways, has not been investigated. In this research, we studied bacterial manipulation of caspase-8 signaling and the significance of caspase-8 to\n                      <jats:italic>C. burnetii<\/jats:italic>\n                      infection, examining bacterial replication, cell death induction, and cytokine signaling. We measured caspase, RIPK, and MLKL activation in\n                      <jats:italic>C. burnetii<\/jats:italic>\n                      -infected tumor necrosis factor alpha (TNF\u03b1)\/cycloheximide-treated THP-1 macrophage-like cells and TNF\u03b1\/ZVAD-treated L929 cells to assess apoptosis and necroptosis signaling. Additionally, we measured\n                      <jats:italic>C. burnetii<\/jats:italic>\n                      replication, cell death, and TNF\u03b1 induction over 12 days in RIPK1-kinase-dead, RIPK3-kinase-dead, or RIPK3-kinase-dead-caspase-8\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      bone marrow-derived macrophages (BMDMs) to understand the significance of caspase-8 and RIPK1\/3 during infection. We found that caspase-8 is inhibited by\n                      <jats:italic>C. burnetii<\/jats:italic>\n                      , coinciding with inhibition of apoptosis and increased susceptibility to necroptosis. Furthermore,\n                      <jats:italic>C. burnetii<\/jats:italic>\n                      replication was increased in BMDMs lacking caspase-8, but not in those lacking RIPK1\/3 kinase activity, corresponding with decreased TNF\u03b1 production and reduced cell death. As TNF\u03b1 is associated with the control of\n                      <jats:italic>C. burnetii<\/jats:italic>\n                      , this lack of a TNF\u03b1 response may allow for the unchecked bacterial growth we saw in caspase-8\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      BMDMs. This research identifies and explores caspase-8 as a key regulator of\n                      <jats:italic>C. burnetii<\/jats:italic>\n                      infection, opening novel therapeutic doors.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00053-24","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T13:12:04Z","timestamp":1717593124000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Caspase-8 activity mediates TNF\u03b1 production and restricts\n                    <i>Coxiella burnetii<\/i>\n                    replication during murine macrophage infection"],"prefix":"10.1128","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1210-9284","authenticated-orcid":false,"given":"Chelsea A.","family":"Osbron","sequence":"first","affiliation":[{"name":"School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Lawson","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nolan","family":"Hanna","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather S.","family":"Koehler","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6394-332X","authenticated-orcid":false,"given":"Alan G.","family":"Goodman","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA"},{"name":"Paul G. 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