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

Abstract

BackgroundEbolavirus (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.Methods/Main findingsWe 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.SignificanceThese 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.

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

“…36 Peritoneal delivery of EBOV causes significant pathology in a variety of different animal models, [37][38][39] with pmacs as potential early targets of infection. 40,41 In these studies, we also extensively utilized a BSL-2 model virus of EBOV, recombinant vesicular stomatitis virus encoding EBOV glycoprotein and GFP in place of the native G glycoprotein (rVSV/EBOV GP). Our laboratory has previously found that rVSV/EBOV GP recapitulates many aspects of EBOV infection both in vitro and in vivo, including virus tropism and responsiveness to proinflammatory and anti-inflammatory cytokines during M infection.…”

Use of biologicals in allergic and type-2 inflammatory diseases during the current COVID-19 pandemic

“…However, IL-4 has a dual role in viral infections due to two different haplotypes in the IL-4 gene. It can promote infections with the Herpes virus and the norovirus [ 43 ] as well as with the Ebola virus, which is related to the coronavirus [ 44 ]. On the other hand, IL-4 can also inhibit viral infections by promoting innate immunity [ 45 , 46 , 47 ].…”

To B or Not to B: Mechanisms of Protection Conferred by rVSV-EBOV-GP and the Roles of Innate and Adaptive Immunity

“…Rapid antiviral innate immunity may also be mediated by EBOV-GP, which has been shown to induce activation of human macrophages and DCs via TLR4 signaling [ 158 , 159 , 160 , 161 ]. This effect of membrane-bound GP (predominant form during vaccination) is distinct from the effects of soluble GP (sGP), which is produced in large quantities during EBOV infection: for instance, in vitro stimulation of DCs and macrophages with sGP thwarts migratory ability and induces a robust cytokine response while simultaneously increasing vascular permeability [ 4 , 162 , 163 ].…”

“…This effect of membrane-bound GP (predominant form during vaccination) is distinct from the effects of soluble GP (sGP), which is produced in large quantities during EBOV infection: for instance, in vitro stimulation of DCs and macrophages with sGP thwarts migratory ability and induces a robust cytokine response while simultaneously increasing vascular permeability [ 4 , 162 , 163 ]. Whereas TLR4 stimulation has been shown to activate DCs and macrophages to differentiate and macrophages to polarize into an anti-inflammatory state [ 6 , 109 , 158 , 161 , 164 , 165 , 166 , 167 ]. Studies in mice demonstrate that vaccination with three doses of purified EBOV-GP confers partial protection (70% survival) from lethal EBOV infection in [ 157 ].…”