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

Many acute viral infections target tissue M phi s, yet the mechanisms of M phi-mediated control of viruses are poorly understood. Here, we report that CD40 expressed by peritoneal M phi 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 phi s required CD154/CD40 interactions that stimulated IL-12 production through TRAF6-dependent signaling. In turn, IL-12 production resulted in IFN-gamma production, which induced proinflammatory polarization of M phi 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 phi-intrinsic CD40 signaling in controlling acute virus infection.

Automated summary

CD40 expression in peritoneal M phi s restricts early infection of a broad range of RNA viruses. CD154/CD40 interactions stimulate IL-12 production, leading to IFN-gamma production and proinflammatory polarization of M phi s, protecting the cells from infection. These CD40-dependent events protect mice against virus challenge.