How filovirus innate immune antagonists abrogates maturation of human monocyte-derived dendritic cells (VIR9P.1141)

Abstract

Abstract Filoviruses, which includes both Ebolavirus (EBOV) and Marburgvirus (MARV), are negative-sense, single-stranded RNA viruses that cause severe hemorrhagic fever in humans with fatality rates that have approach 90% in some outbreaks. Antigen presenting cells such as dendritic cells (DCs) are early and sustained targets of filovirus infection in vivo, and in vitro filovirus infection potently blocks DC maturation and function. Both EBOV-VP35 and MARV-VP35 proteins block IFN-β production, in part, by inhibiting of the viral RNA sensor RIG-I. Further, EBOV-VP24 can inhibit the production of interferon-stimulated genes (ISGs) by blocking type I IFN signaling. We used a lentivirus-based expression system to determine the impact of these filoviral innate immune inhibitors on DCs. Our data demonstrate that EBOV-VP35 and MARV-VP35 can each suppress not only IFN-α/β production but also proinflammatory responses following stimulation of MDDCs with Sendai virus (SeV) or encephalomyocarditis virus (EMCV). Furthermore, either EBOV-VP35 or MARV-VP35 alone is sufficient to inhibit human DC maturation upon SeV infection. EBOV-VP24, despite having the ability to suppress ISG production, fails to block DC maturation induced by SeV or EMCV. Our work suggest that suppression of innate immune response by filoviral VP35s is sufficient to explain the potent blockade of DC function seen in filovirus infection and could be a potential the immune blockade during infection.