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Frontline Science: CD40 signaling restricts RNA virus replication in M?s, leading to rapid innate immune control of acute virus infection.


ABSTRACT: Many acute viral infections target tissue M?s, yet the mechanisms of M?-mediated control of viruses are poorly understood. Here, we report that CD40 expressed by peritoneal M?s restricts early infection of a broad range of RNA viruses. Loss of CD40 expression enhanced virus replication as early as 12-24 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?s required CD154/CD40 interactions that stimulated IL-12 production through TRAF6-dependent signaling. In turn, IL-12 production resulted in IFN-? production, which induced proinflammatory polarization of M?s, protecting the cells from infection. These CD40-dependent events protected mice against virus challenge. CD40-/- 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?-intrinsic CD40 signaling in controlling acute virus infection.

SUBMITTER: Rogers KJ 

PROVIDER: S-EPMC7774454 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Frontline Science: CD40 signaling restricts RNA virus replication in Mϕs, leading to rapid innate immune control of acute virus infection.

Rogers Kai J KJ   Shtanko Olena O   Stunz Laura L LL   Mallinger Laura N LN   Arkee Tina T   Schmidt Megan E ME   Bohan Dana D   Brunton Bethany B   White Judith M JM   Varga Steve M SM   Butler Noah S NS   Bishop Gail A GA   Maury Wendy W  

Journal of leukocyte biology 20200522 2


Many acute viral infections target tissue Mϕs, yet the mechanisms of Mϕ-mediated control of viruses are poorly understood. Here, we report that CD40 expressed by peritoneal Mϕs restricts early infection of a broad range of RNA viruses. Loss of CD40 expression enhanced virus replication as early as 12-24 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 (EBO  ...[more]

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