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.

It has been reported that in addition to preventing IRF3 phosphorylation and activation by blocking RIG-I viral RNA sensing, EBOV VP35 also prevents IRF3 phosphorylation by directly blocking the access of the kinases IKKε and TBK-1 to unphosphorylated IRF3 (Prins et al., 2009) . To determine if NTZ can directly augment IRF3's activity, we next transfected HEK293T cells with a plasmid encoding phosphomimetic IRF3, which is able to drive IFN-b mRNA expression in the absence of proximal components of the RLR signaling pathway (Lin et al., 1998) . As shown in Figure 1D , NTZ enhanced IRF3-induced IFN-b reporter activity in a dose-dependent manner. Furthermore, we also found that NTZ enhanced type I IFN-induced transcription of the ISGs Mx1, IFI27, and IFITM3 ( Figure 1E ). Thus, NTZ broadly enhances signaling downstream of the RLR and IFN-b signaling pathways in addition to acting as an agonist for viral RNA sensors acting at the proximal part of the pathway in the cytoplasm.