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 also been previously reported that NTZ induces phosphorylation of PKR in different cell lines. However, weak NTZ-induced PKR phosphorylation was only observed in one study after 72 h of 0.5 or 5 mM NTZ exposure in human hepatoma cells harboring an hepatitis C virus (HCV) replicon (Elazar et al., 2009) , and after 24 h in a bovine kidney cell line with 25 mM, but not 10 mM, NTZ in another study (Ashiru et al., 2014) . Furthermore, in both reports, no direct functional link between putative PKR phosphorylation by NTZ and its antiviral activity was demonstrated, thus leaving unverified the functional importance of PKR, or its phosphorylation status, for NTZ's ability to suppress replication of PKR-sensitive viruses. By contrast, our demonstration that the effect of NTZ on EBOV growth is markedly impaired in cells where PKR expression has been ablated directly links NTZ pretreatment for 4 h before EBOV infection to PKR restriction of EBOV growth.