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.
Highlights
The genus Ebolavirus is composed of five viruses: Zaire ebolavirus (EBOV), Sudan ebolavirus, Bundibugyo ebolavirus, Tai Forest ebolavirus and Reston ebolavirus
We show that macrophages stimulated with the immunomodulatory cytokines IL-4 and IL-13 are significantly more susceptible than unstimulated cells to a model virus that expresses the Ebola virus glycoprotein
Our studies argue for the critical importance of the macrophages and their response to immunomodulatory cytokines in controlling the pathological consequences of Ebola virus glycoprotein-dependent infections and highlight an important aspect of filovirus/ macrophage interaction that if controlled could decrease virus pathogenesis
Summary
The genus Ebolavirus is composed of five viruses: Zaire ebolavirus (EBOV), Sudan ebolavirus, Bundibugyo ebolavirus, Tai Forest ebolavirus and Reston ebolavirus. All but Reston are pathogenic to humans and endemic in Africa. This genus is one of two extant genera that compose the family Filoviridae, with Marburgvirus being the other. Ebola virus disease (EVD) in humans is difficult to diagnose as it results initially in nonspecific symptoms common to a number of infectious agents endemic to Africa. No targeted therapeutics have come to market, with little more than supportive care currently available to patients [4]. Ebolavirus (EBOV) outbreaks, while sporadic, cause tremendous morbidity and mortality. 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
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