Frontline Science: CD40 signaling restricts RNA virus replication in Mϕs, 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.

Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs against Ebola Virus In Vivo

“…Although apilimod has potent activity against EBOV in cell cultures [ 32 , 41 , 42 ] and has a human C max /IC 50 >1 ( Supplemental Table S5 ) suggesting potential activity in vivo, in a first test as a single agent in female C57BL/6 mice challenged with mouse-adapted EBOV (ma-EBOV), apilimod provided no survival advantage ( Supplemental Figure S5 ). This was likely because apilimod is known to inhibit IL12/23 production [ 43 , 44 ], thereby interfering with IL12-mediated inhibition of EBOV infection (via interferon γ production) in macrophages [ 45 ], which are key targets of EBOV infection [ 2 ]. Hence, the components chosen for pairwise tests in mice were bepridil, sertraline and toremifene in the combinations (bepridil + sertraline) and (sertraline + toremifene).…”

Prognostic impacts of soluble immune checkpoint regulators and cytokines in patients with SARS-CoV-2 infection

“…As a member of the TNF superfamily, CD27 includes both costimulatory and apoptosis-inducing molecules, and its stimulation promotes natural killer/T cell survival and effector functions, which are required for the proliferation of various viruses ( 18 – 20 ). In addition, CD40 is important in the IFN-I response, parasitemia control, and host survival ( 21 ), and its signaling in macrophages inhibit acute viral replication at the early stages of infection ( 22 ). In SARS-CoV-2 infection, CD40 has been used as a subunit vaccine targeting viral antigens to CD40-expressing antigen-presenting cells ( 23 ).…”

Compound FC-10696 Inhibits Egress and Spread of Marburg Virus

“…Flag-tagged mVP40 plasmid was kindly provided by S. Becker (Institut für Virologie, Marburg, Germany). Monocyte-derived human macrophages (MDMs) were isolated as described previously (47,48). Peripheral blood was collected from healthy donors according to University of Texas Health approved IRB protocol 20180013HU.…”