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

J Leukoc Biol. 2021 Feb;109(2):309-325. doi: 10.1002/JLB.4HI0420-285RR. Epub 2020 May 22.


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.

Keywords: CD40; CD40 signaling; Ebola virus; IFN-γ; IL-12; Mϕ; RNA virus; TRAF6; filovirus; innate immunity; peritoneum; virus restriction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Disease
  • Animals
  • CD40 Antigens / metabolism*
  • CD40 Ligand / metabolism
  • Ebolavirus / physiology
  • Glycoproteins / immunology
  • Humans
  • Immunity, Innate*
  • Interferon-gamma / metabolism
  • Interleukin-12 / biosynthesis
  • Macrophages / immunology*
  • Macrophages / virology*
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Peritoneum / pathology
  • Peritoneum / virology
  • RNA Viruses / physiology*
  • Signal Transduction*
  • TNF Receptor-Associated Factor 6 / metabolism
  • Virus Diseases / immunology*
  • Virus Diseases / virology
  • Virus Replication / physiology*


  • CD40 Antigens
  • Glycoproteins
  • TNF Receptor-Associated Factor 6
  • CD40 Ligand
  • Interleukin-12
  • Interferon-gamma