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Here, we report that CD40 expressed by peritoneal M\u03d5s restricts early infection of a broad range of RNA viruses. Loss of CD40 expression enhanced virus replication as early as 12\u201324 h of infection and, conversely, stimulation of CD40 signaling with an agonistic Ab blocked infection. With peritoneal cell populations infected with the filovirus, wild-type (WT) Ebola virus (EBOV), or a BSL2 model virus, recombinant vesicular stomatitis virus encoding Ebola virus glycoprotein (rVSV\/EBOV GP), we examined the mechanism conferring protection. Here, we demonstrate that restricted virus replication in M\u03d5s required CD154\/CD40 interactions that stimulated IL-12 production through TRAF6-dependent signaling. In turn, IL-12 production resulted in IFN-\u03b3 production, which induced proinflammatory polarization of M\u03d5s, protecting the cells from infection. These CD40-dependent events protected mice against virus challenge. CD40\u2212\/\u2212 mice were exquisitely sensitive to intraperitoneal challenge with a dose of rVSV\/EBOV GP that was sublethal to CD40+\/+ mice, exhibiting viremia within 12 h of infection and rapidly succumbing to infection. This study identifies a previously unappreciated role for M\u03d5-intrinsic CD40 signaling in controlling acute virus infection.<\/jats:p>","DOI":"10.1002\/jlb.4hi0420-285rr","type":"journal-article","created":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T09:55:02Z","timestamp":1590141302000},"page":"309-325","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Frontline Science: CD40 signaling restricts RNA virus replication in M\u03d5s, leading to rapid innate immune control of acute virus infection"],"prefix":"10.1093","volume":"109","author":[{"given":"Kai J","family":"Rogers","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Iowa , Iowa City, Iowa , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olena","family":"Shtanko","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions, Texas Biomedical Research Institute , San 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Bohan","sequence":"additional","affiliation":[{"name":"Interdisciplinary Graduate Program in Immunology, University of Iowa , Iowa City, Iowa , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Brunton","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Iowa , Iowa City, Iowa , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0532-996X","authenticated-orcid":true,"given":"Judith M","family":"White","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Virginia , Charlottesville, Virginia , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7332-4290","authenticated-orcid":true,"given":"Steve M","family":"Varga","sequence":"additional","affiliation":[{"name":"Department of 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