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.

The phosphatase GADD34 selectively promotes IFN-b translation in the context of host global translational shutdown following PKR-dependent eIF2a phosphorylation or stress pathway activation (Dalet et al., 2017). NTZ has previously been shown to induce low levels of endoplasmic reticulum stress (Ashiru et al., 2014) and to promote the translation of the transcription factor ATF4 (Elazar et al., 2009), which during translational inhibition is a transcriptional activator of GADD34 gene expression (Ma and Hendershot, 2003) . We thus investigated whether NTZ affected GADD34 expression. We treated A549 cells with increasing concentrations of NTZ for 4 h and measured GADD34 mRNA levels. NTZ strongly induced GADD34 mRNA synthesis in an NTZ concentration-dependent manner ( Figure 3E ). We note that maximal GADD34 transcription was detected between 4 and 8 h post-NTZ stimulation of A549 cells (not shown).