The FDA-Approved Oral Drug Nitazoxanide Amplifies Host Antiviral Responses and Inhibits Ebola Virus

Jasenosky, Luke D.; Cadena, Cristhian; Mire, Chad E.; Borisevich, Viktoriya; Haridas, Viraga; Ranjbar, Shahin; Nambu, Aya; Bavari, Sina; Soloveva, Veronica; Sadukhan, Supriya; Cassell, Gail H.; Geisbert, Thomas W.; Hur, Sun; Goldfeld, Anne E.

Pathogenic viruses have evolved a diverse array of mechanisms to avoid or impair the host innate immune antiviral response (Unterholzner and Almine, 2019) , particularly by evading those pathways that result in type I interferon (IFN) production and signaling (Garcia-Sastre, 2017) . For example, Ebola virus (EBOV) relies on its structural protein VP35 to inhibit viral double-stranded RNA (dsRNA) sensing by retinoic-acid-inducible protein I (RIG-I) (Cardenas et al., 2006; Leung et al., 2010; Luthra et al., 2013) and the IFN-inducible double-stranded (ds)RNA sensor protein kinase R (PKR) (Feng et al., 2007; Schumann et al., 2009) , thus avoiding the triggering and amplification of the host type I IFN response. The critical role played by VP35 in productive EBOV infection was underscored by the finding that mutations introduced into VP35 that disrupted its ability to sequester viral RNA intermediates, which did not affect its function in EBOV replication, resulted in increased type I IFN induction in vitro and severely attenuated viral growth in vivo in mice (Hartman et al., 2008) and guinea pigs . A host-directed therapy that could overcome this potent VP35-dependent EBOV immune evasion strategy would thus be particularly useful.