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

Here, we show that the US Food and Drug Administration-approved oral drug nitazoxanide (NTZ) broadly amplifies the host innate immune response to viruses and inhibits Ebola virus (EBOV) replication. We find that NTZ enhances retinoic-acid-inducible protein I (RIG-I)-like-receptor, mitochondrial anti...

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Published in:	iScience Vol. 19; pp. 1279 - 1290
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 27-09-2019 Elsevier
Subjects:	Immune Response Mechanism of Action Pathogenic Organism Viral Microbiology Mechanism of Action Pathogenic Organism Viral Microbiology Immune Response
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Summary:	Here, we show that the US Food and Drug Administration-approved oral drug nitazoxanide (NTZ) broadly amplifies the host innate immune response to viruses and inhibits Ebola virus (EBOV) replication. We find that NTZ enhances retinoic-acid-inducible protein I (RIG-I)-like-receptor, mitochondrial antiviral signaling protein, interferon regulatory factor 3, and interferon activities and induces transcription of the antiviral phosphatase GADD34. NTZ significantly inhibits EBOV replication in human cells through its effects on RIG-I and protein kinase R (PKR), suggesting that it counteracts EBOV VP35 protein's ability to block RIG-I and PKR sensing of EBOV. NTZ also inhibits a second negative-strand RNA virus, vesicular stomatitis virus (VSV), through RIG-I and GADD34, but not PKR, consistent with VSV's distinct host innate immune evasion mechanisms. Thus, NTZ counteracts varied virus-specific immune evasion strategies by generally enhancing the RNA sensing and interferon axis that is triggered by foreign cytoplasmic RNA exposure, and holds promise as an oral therapy against EBOV. [Display omitted] •NTZ amplifies RNA sensor and type I interferon activities and induces GADD34 expression•NTZ inhibits infectious Ebola virus (EBOV) via RIG-I and PKR, but not GADD34•NTZ inhibits a second negative-strand RNA virus, VSV, via RIG-I and GADD34, but not PKR•NTZ holds promise as an oral therapy against EBOV Mechanism of Action; Pathogenic Organism; Immune Response; Viral Microbiology
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Merck Research Laboratories, Boston, MA 02115, USA Lead Contact Present address: Profectus Biosciences, Pearl River, NY 10965, USA
ISSN:	2589-0042 2589-0042
DOI:	10.1016/j.isci.2019.07.003