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

Kai J Rogers; Olena Shtanko; Laura L Stunz; Laura N Mallinger; Tina Arkee; Megan E Schmidt; Dana Bohan; Bethany Brunton; Judith M White; Steve M Varga; Noah S Butler; Gail A Bishop; Wendy Maury

doi:10.1002/JLB.4HI0420-285RR

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

Journal article

Peer reviewed

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

Kai J Rogers, Olena Shtanko, Laura L Stunz, Laura N Mallinger, Tina Arkee, Megan E Schmidt, Dana Bohan, Bethany Brunton, Judith M White, Steve M Varga, …

Journal of leukocyte biology, Vol.109(2), pp.309-325

02/2021

DOI: 10.1002/JLB.4HI0420-285RR

PMCID: PMC7774454

PMID: 32441445

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Abstract

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.

Signal Transduction

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, Inbred C57BL

Models, Biological

Peritoneum - pathology

Peritoneum - virology

RNA Viruses - physiology

TNF Receptor-Associated Factor 6 - metabolism

Virus Diseases - immunology

Virus Diseases - virology

Virus Replication - physiology

Details

Title: Subtitle: Frontline Science: CD40 signaling restricts RNA virus replication in Mϕs, leading to rapid innate immune control of acute virus infection
Creators: Kai J Rogers - University of Iowa
Olena Shtanko - Texas Biomedical Research Institute
Laura L Stunz - University of Iowa
Laura N Mallinger - University of Iowa
Tina Arkee - University of Iowa
Megan E Schmidt - University of Iowa
Dana Bohan - University of Iowa
Bethany Brunton - University of Iowa
Judith M White - University of Virginia
Steve M Varga - Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, USA
Noah S Butler - University of Iowa
Gail A Bishop - University of Iowa
Wendy Maury - University of Iowa
Resource Type: Journal article
Publication Details: Journal of leukocyte biology, Vol.109(2), pp.309-325
DOI: 10.1002/JLB.4HI0420-285RR
PMID: 32441445
PMCID: PMC7774454
NLM abbreviation: J Leukoc Biol
ISSN: 0741-5400
eISSN: 1938-3673
Grant note: T32 GM067795 / NIGMS NIH HHS P30 ES005605 / NIEHS NIH HHS R21 AI139902 / NIAID NIH HHS R21 AI144215 / NIAID NIH HHS R01 AI124093 / NIAID NIH HHS RO1AI124093 / NIH HHS R01 AI127481 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS R01AI125446 / NIH HHS University of Iowa Department of Microbiology and Immunology Developmental Grant R21 AI144215 / NIH HHS I01 BX001702 / BLRD VA T32GM007337 / NIH HHS P30 CA086862 / NCI NIH HHS R21 AI139902 / NIH HHS T32 AI007511 / NIAID NIH HHS R21 AI119163 / NIAID NIH HHS R01 AI134733 / NIAID NIH HHS AI114776 / NIH HHS I01 BX001702 / NIH HHS R01AI127481 / NIH HHS AI119163 / NIH HHS R01 AI114776 / NIAID NIH HHS R01 AI125446 / NIAID NIH HHS
Language: English
Date published: 02/2021
Academic Unit: Molecular Physiology and Biophysics; Graduate College Admin and Gen; Microbiology and Immunology; President; Pathology; Fraternal Order of Eagles Diabetes Research Center; Community and Behavioral Health
Record Identifier: 9984297432602771

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