CD40 Signaling in Mice Elicits a Broad Antiviral Response Early during Acute Infection with RNA Viruses.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101509722 Publication Model: Electronic Cited Medium: Internet ISSN: 1999-4915 (Electronic) Linking ISSN: 19994915 NLM ISO Abbreviation: Viruses Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

CD40 Antigens*/metabolism ; RNA Viruses* ; RNA Virus Infections*/immunology; Animals ; Mice ; Interferon-gamma ; Macrophages

Macrophages are critical in the pathogenesis of a diverse group of viral pathogens, both as targets of infection and for eliciting primary defense mechanisms. Our prior in vitro work identified that CD40 signaling in murine peritoneal macrophages protects against several RNA viruses by eliciting IL-12, which stimulates the production of interferon gamma (IFN-γ). Here, we examine the role of CD40 signaling in vivo. We show that CD40 signaling is a critical, but currently poorly appreciated, component of the innate immune response using two distinct infectious agents: mouse-adapted influenza A virus (IAV, PR8) and recombinant VSV encoding the Ebola virus glycoprotein (rVSV-EBOV GP). We find that stimulation of CD40 signaling decreases early IAV titers, whereas loss of CD40 elevated early titers and compromised lung function by day 3 of infection. Protection conferred by CD40 signaling against IAV is dependent on IFN-γ production, consistent with our in vitro studies. Using rVSV-EBOV GP that serves as a low-biocontainment model of filovirus infection, we demonstrate that macrophages are a CD40-expressing population critical for protection within the peritoneum and T-cells are the key source of CD40L (CD154). These experiments reveal the in vivo mechanisms by which CD40 signaling in macrophages regulates the early host responses to RNA virus infection and highlight how CD40 agonists currently under investigation for clinical use may function as a novel class of broad antiviral treatments.

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IK6 BX005392 United States BX BLRD VA; R01 AI127481 United States AI NIAID NIH HHS; T32 AI007533 United States AI NIAID NIH HHS; R01 AI125446 United States AI NIAID NIH HHS; R21AI133215, R01 AI1134733, AI125446, AI127481, AI167058 United States NH NIH HHS; R01 AI134733 United States AI NIAID NIH HHS; P30 ES005605 United States ES NIEHS NIH HHS; R01 AI167058 United States AI NIAID NIH HHS

Keywords: CD154; CD40; Ebola virus; IL-12; enveloped virus; filovirus; influenza A virus; interferon gamma; macrophage; peritoneum; recombinant vesicular stomatitis virus

0 (CD40 Antigens)
82115-62-6 (Interferon-gamma)

Date Created: 20230628 Date Completed: 20230707 Latest Revision: 20240127

20240127

PMC10305536

10.3390/v15061353

37376652