IL-4/IL-13 polarization of macrophages enhances Ebola virus glycoprotein-dependent infection

Kai J Rogers; Bethany Brunton; Laura Mallinger; Dana Bohan; Kristina M Sevcik; Jing Chen; Natalie Ruggio; Wendy Maury

doi:10.1371/journal.pntd.0007819

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IL-4/IL-13 polarization of macrophages enhances Ebola virus glycoprotein-dependent infection

Journal article

Open access

Peer reviewed

IL-4/IL-13 polarization of macrophages enhances Ebola virus glycoprotein-dependent infection

Kai J Rogers, Bethany Brunton, Laura Mallinger, Dana Bohan, Kristina M Sevcik, Jing Chen, Natalie Ruggio and Wendy Maury

PLoS neglected tropical diseases, Vol.13(12), pp.e0007819-e0007819

12/2019

DOI: 10.1371/journal.pntd.0007819

PMCID: PMC6905523

PMID: 31825972

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Abstract

Ebolavirus (EBOV) outbreaks, while sporadic, cause tremendous morbidity and mortality. No therapeutics or vaccines are currently licensed; however, a vaccine has shown promise in clinical trials. A critical step towards development of effective therapeutics is a better understanding of factors that govern host susceptibility to this pathogen. As macrophages are an important cell population targeted during virus replication, we explore the effect of cytokine polarization on macrophage infection. We utilized a BSL2 EBOV model virus, infectious, recombinant vesicular stomatitis virus encoding EBOV glycoprotein (GP) (rVSV/EBOV GP) in place of its native glycoprotein. Macrophages polarized towards a M2-like anti-inflammatory state by combined IL-4 and IL-13 treatment were more susceptible to rVSV/EBOV GP, but not to wild-type VSV (rVSV/G), suggesting that EBOV GP-dependent entry events were enhanced by these cytokines. Examination of RNA expression of known surface receptors that bind and internalize filoviruses demonstrated that IL-4/IL-13 stimulated expression of the C-type lectin receptor DC-SIGN in human macrophages and addition of the competitive inhibitor mannan abrogated IL-4/IL-13 enhanced infection. Two murine DC-SIGN-like family members, SIGNR3 and SIGNR5, were upregulated by IL-4/IL-13 in murine macrophages, but only SIGNR3 enhanced virus infection in a mannan-inhibited manner, suggesting that murine SIGNR3 plays a similar role to human DC-SIGN. In vivo IL-4/IL-13 administration significantly increased virus-mediated mortality in a mouse model and transfer of ex vivo IL-4/IL-13-treated murine peritoneal macrophages into the peritoneal cavity of mice enhanced pathogenesis. These studies highlight the ability of macrophage polarization to influence EBOV GP-dependent virus replication in vivo and ex vivo, with M2a polarization upregulating cell surface receptor expression and thereby enhancing virus replication. Our findings provide an increased understanding of the host factors in macrophages governing susceptibility to filoviruses and identify novel murine receptors mediating EBOV entry.

Animals

Disease Models, Animal

Ebolavirus - physiology

Female

Hemorrhagic Fever, Ebola - pathology

Hemorrhagic Fever, Ebola - virology

Host-Pathogen Interactions

Interleukin-13 - metabolism

Interleukin-4 - metabolism

Macrophages - immunology

Macrophages - virology

Male

Mice, Inbred C57BL

Virus Internalization

Details

Title: Subtitle: IL-4/IL-13 polarization of macrophages enhances Ebola virus glycoprotein-dependent infection
Creators: Kai J Rogers - University of Iowa
Bethany Brunton - Department of Microbiology and Immunology, University of Iowa, Iowa City, IA United States of America
Laura Mallinger - University of Iowa, Microbiology and Immunology
Dana Bohan - Department of Microbiology and Immunology, University of Iowa, Iowa City, IA United States of America
Kristina M Sevcik - Department of Microbiology and Immunology, University of Iowa, Iowa City, IA United States of America
Jing Chen - Department of Microbiology and Immunology, University of Iowa, Iowa City, IA United States of America
Natalie Ruggio - University of Iowa, Microbiology and Immunology
Wendy Maury - University of Iowa, Microbiology and Immunology
Resource Type: Journal article
Publication Details: PLoS neglected tropical diseases, Vol.13(12), pp.e0007819-e0007819
DOI: 10.1371/journal.pntd.0007819
PMID: 31825972
PMCID: PMC6905523
NLM abbreviation: PLoS Negl Trop Dis
ISSN: 1935-2735
eISSN: 1935-2735
Grant note: T32 GM067795 / NIGMS NIH HHS T32 AI007343 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS R01 AI077519 / NIAID NIH HHS
Language: English
Date published: 12/2019
Academic Unit: Microbiology and Immunology
Record Identifier: 9984228051002771

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