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

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Kai J. Rogers¹  Olena Shtanko²  Laura L. Stunz¹  Laura N. Mallinger¹  Tina Arkee³  Megan E. Schmidt³  Dana Bohan³  Bethany Brunton¹  Judith M. White⁴  Steve M. Varga¹  Noah S. Butler¹  Gail A. Bishop¹  Wendy Maury¹ 

[1] Department of Microbiology and Immunology, University of Iowa;Host-Pathogen Interactions, Texas Biomedical Research Institute;Interdisciplinary Graduate Program in Immunology, University of Iowa;Department of Cell Biology, University of Virginia;Department of Internal Medicine, University of Iowa;Iowa City VA Health Care System

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

DOI  :  10.1002/JLB.4HI0420-285RR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

CC BY