189: Differences in cytokine responses during infection with high and low pathogenic Ebola viruses

Abstract

To date five Ebolavirus species have been identified, differing in pathogenicity. The highly pathogenic Zaire ebolavirus (EBOV) causes a hemorrhagic disease in humans with case fatality rates up to 90%. A hallmark of EBOV infection is a dysregulated immune response, including high levels of cytokines. In contrast, Reston ebolavirus (RESTV) seems to be nonpathogenic in humans, as only asymptomatic cases of RESTV infection in humans have been reported. The mechanisms of protection against RESTV in humans are not yet understood. As cytokines might play a role in the pathogenesis of EBOV infection, we analyzed the cytokine response in EBOV- and RESTV-infected human macrophages and dendritic cells. These cells not only orchestrate innate and adaptive immune responses but are also early targets of Ebolaviruses. We observed degradation of I κ Bα and nuclear translocation of p65 in EBOV-infected macrophages, indicating activation of NFκB signaling. qRT-PCR and Luminex assays revealed induction of selected cytokines in EBOV-infected macrophages. Most analyzed cytokines and chemokines were upregulated in EBOV infection at 6 hpi or later, whereas others, including IL10, did not show increased secretion levels. In contrast, p65 was not translocated into the nucleus in RESTV-infected macrophages and no significant changes in cytokine mRNA levels or secreted protein levels were observed. To investigate if this effect is due to inhibition of pro-inflammatory signaling pathways, RESTV-infected macrophages were treated with LPS at 1 dpi and cytokine production was determined. Similar levels of pro-inflammatory cytokines, including IL6 and TNFα, were detected in RESTV-infected and LPS-treated macrophages compared to non-infected LPS-treated cells, suggesting that RESTV is not able to inhibit LPS-mediated cytokine induction. Our data support the hypothesis that high pathogenicity correlates with high cytokine levels in Ebolavirus infection. Currently we are investigating which cellular signaling pathways are involved in the observed differential cytokine induction in EBOV versus RESTV infection.