1. Frontline Science: CD40 signaling restricts RNA virus replication in Mϕs, leading to rapid innate immune control of acute virus infection.
- Author
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Rogers KJ, Shtanko O, Stunz LL, Mallinger LN, Arkee T, Schmidt ME, Bohan D, Brunton B, White JM, Varga SM, Butler NS, Bishop GA, and Maury W
- Subjects
- Acute Disease, Animals, CD40 Ligand metabolism, Ebolavirus physiology, Glycoproteins immunology, Humans, Interferon-gamma metabolism, Interleukin-12 biosynthesis, Mice, Inbred C57BL, Models, Biological, Peritoneum pathology, Peritoneum virology, TNF Receptor-Associated Factor 6 metabolism, Virus Diseases virology, Mice, CD40 Antigens metabolism, Immunity, Innate, Macrophages immunology, Macrophages virology, RNA Viruses physiology, Signal Transduction, Virus Diseases immunology, Virus Replication physiology
- Abstract
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 (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 Mϕs required CD154/CD40 interactions that stimulated IL-12 production through TRAF6-dependent signaling. In turn, IL-12 production resulted in IFN-γ production, which induced proinflammatory polarization of Mϕs, 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 Mϕ-intrinsic CD40 signaling in controlling acute virus infection., (©2020 Society for Leukocyte Biology.)- Published
- 2021
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