Novel activities by ebolavirus and marburgvirus interferon antagonists revealed using a standardized in vitro reporter system

- We standardized functional assays of IFN antagonists from all isolated filoviruses.
- Ravn virus VP35 activity was closer to that of ebolaviruses than to Marburg virus.
- Taï Forest and Sudan virus VP40 proteins displayed moderate inhibitory activities.
- VP24 of most ebolaviruses and two VP40 proteins found to block IFN induction.
- VP24 of human-apathogenic Reston virus exhibited greatly impaired antagonism.

Filoviruses are highly lethal in humans and nonhuman primates, likely due to potent antagonism of host interferon (IFN) responses early in infection. Filoviral protein VP35 is implicated as the major IFN induction antagonist, while Ebola virus (EBOV) VP24 or Marburg virus (MARV) VP40 are known to block downstream IFN signaling. Despite progress elucidating EBOV and MARV antagonist function, those for most other filoviruses, including Reston (RESTV), Sudan (SUDV), Taï Forest (TAFV), Bundibugyo (BDBV) and Ravn (RAVV) viruses, remain largely neglected. Thus, using standardized vectors and reporter assays, we characterized activities by each IFN antagonist from all known ebolavirus and marburgvirus species side-by-side. We uncover noncanonical suppression of IFN induction by ebolavirus VP24, differing potencies by MARV and RAVV proteins, and intriguingly, weaker antagonism by VP24 of RESTV. These underlying molecular explanations for differential virulence in humans could guide future investigations of more-neglected filoviruses as well as treatment and vaccine studies.

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