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.

Nitazoxanide (NTZ) is an oral US Food and Drug Administration (FDA)-approved drug that has been used in millions of adults and children since 2004 with minimal adverse side effects for the treatment of Giardiaand Cryptosporidium-associated diarrhea, including in patients co-infected with HIV (Doumbo et al., 1997; Hussar, 2004; Rossignol et al., 1998) . NTZ and its circulating metabolite tizoxanide (TIZ) have also been reported to inhibit a diverse array of viruses in tissue culture and in small animal models (Rossignol, 2014) . In humans, NTZ reduces symptom duration of uncomplicated influenza (Haffizulla et al., 2014) , viral gastroenteritis (Rossignol and El-Gohary, 2006) , and rotaviral diarrhea . Several mechanisms have been proposed to contribute to NTZ's activity against specific viruses (Ashiru et al., 2014; La Frazia et al., 2013; Li et al., 2017; Piacentini et al., 2018; Rossignol et al., 2009b; Sekiba et al., 2018) , including studies showing enhancement or induction of IFN-stimulated gene (ISG) expression by NTZ (Gekonge et al., 2015; Petersen et al., 2016; Trabattoni et al., 2016) and studies showing a weak association between NTZ and PKR activation (Ashiru et al., 2014; Elazar et al., 2009 ). However, no functional link between NTZ's antiviral activity and any specific ISG or with PKR has been demonstrated, and the molecular mechanisms underlying its broad-spectrum antiviral effects on host cells remain unknown.