Sirtuin Inhibitors Are Broadly Antiviral against Arboviruses

ABSTRACT Arthropod-borne viruses are diverse pathogens and are often associated with human disease. These viruses span multiple genera, including flaviviruses, alphaviruses, and bunyaviruses. In a high-throughput drug screen, we found that tenovin-1 was antiviral against the flaviviruses Zika virus...

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Autores principales:	Brent A. Hackett, Mark Dittmar, Elisha Segrist, Nathan Pittenger, Julie To, Trevor Griesman, Beth Gordesky-Gold, David C. Schultz, Sara Cherry
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	alphavirus arbovirus bunyavirus flavivirus sirtinol sirtuin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/443ecdb4a429445e8eefee560540f5c9
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spelling	oai:doaj.org-article:443ecdb4a429445e8eefee560540f5c92021-11-15T16:22:09ZSirtuin Inhibitors Are Broadly Antiviral against Arboviruses10.1128/mBio.01446-192150-7511https://doaj.org/article/443ecdb4a429445e8eefee560540f5c92019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01446-19https://doaj.org/toc/2150-7511ABSTRACT Arthropod-borne viruses are diverse pathogens and are often associated with human disease. These viruses span multiple genera, including flaviviruses, alphaviruses, and bunyaviruses. In a high-throughput drug screen, we found that tenovin-1 was antiviral against the flaviviruses Zika virus and dengue virus. Tenovin-1 is a sirtuin inhibitor, and here we found that inhibition of sirtuins, but not inhibition of the related histone deacetylases, is potently antiviral against diverse arboviruses. Sirtuin inhibitors block infection of arboviruses in multiple human cell types. We found that sirtuin inhibitors arrest infection downstream of entry but that they do so at an early step, preventing the accumulation of viral RNA and protein. However, sirtuin inhibitors had no impact on the replication of flaviviral replicons, suggesting a defect in the establishment of replication. Consistent with this, we found that sirtuin inhibitors impacted double-stranded RNA (dsRNA) accumulation during flaviviral infection. Since these viruses infect vector insects, we also tested whether sirtuin inhibitors impacted infection of adult flies and found that these inhibitors blocked infection; therefore, they target highly conserved facets of replication. Taken together, these results suggest that sirtuin inhibitors represent a new class of potent host-targeting antivirals. IMPORTANCE Arthropod-borne viruses are diverse pathogens and are associated with human disease. Through high-throughput drug screening, we found that sirtuin inhibitors are potently antiviral against diverse arboviruses, including flaviviruses such as West Nile virus, bunyaviruses such as Rift Valley fever virus, and alphaviruses such as chikungunya virus. Sirtuin inhibitors block infection of these viruses in multiple human cell types. Moreover, we found that sirtuin inhibitors arrest infection downstream of entry but that they do so at an early step, preventing the accumulation of viral RNA and protein. Since these viruses infect vector insects, we also tested whether sirtuin inhibitors impacted infection of adult flies and found that these inhibitors blocked infection; therefore, they target highly conserved facets of replication. Taken together, these results suggest that sirtuin inhibitors represent a new class of potent host-targeting antivirals.Brent A. HackettMark DittmarElisha SegristNathan PittengerJulie ToTrevor GriesmanBeth Gordesky-GoldDavid C. SchultzSara CherryAmerican Society for MicrobiologyarticlealphavirusarbovirusbunyavirusflavivirussirtinolsirtuinMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	alphavirus arbovirus bunyavirus flavivirus sirtinol sirtuin Microbiology QR1-502
spellingShingle	alphavirus arbovirus bunyavirus flavivirus sirtinol sirtuin Microbiology QR1-502 Brent A. Hackett Mark Dittmar Elisha Segrist Nathan Pittenger Julie To Trevor Griesman Beth Gordesky-Gold David C. Schultz Sara Cherry Sirtuin Inhibitors Are Broadly Antiviral against Arboviruses
description	ABSTRACT Arthropod-borne viruses are diverse pathogens and are often associated with human disease. These viruses span multiple genera, including flaviviruses, alphaviruses, and bunyaviruses. In a high-throughput drug screen, we found that tenovin-1 was antiviral against the flaviviruses Zika virus and dengue virus. Tenovin-1 is a sirtuin inhibitor, and here we found that inhibition of sirtuins, but not inhibition of the related histone deacetylases, is potently antiviral against diverse arboviruses. Sirtuin inhibitors block infection of arboviruses in multiple human cell types. We found that sirtuin inhibitors arrest infection downstream of entry but that they do so at an early step, preventing the accumulation of viral RNA and protein. However, sirtuin inhibitors had no impact on the replication of flaviviral replicons, suggesting a defect in the establishment of replication. Consistent with this, we found that sirtuin inhibitors impacted double-stranded RNA (dsRNA) accumulation during flaviviral infection. Since these viruses infect vector insects, we also tested whether sirtuin inhibitors impacted infection of adult flies and found that these inhibitors blocked infection; therefore, they target highly conserved facets of replication. Taken together, these results suggest that sirtuin inhibitors represent a new class of potent host-targeting antivirals. IMPORTANCE Arthropod-borne viruses are diverse pathogens and are associated with human disease. Through high-throughput drug screening, we found that sirtuin inhibitors are potently antiviral against diverse arboviruses, including flaviviruses such as West Nile virus, bunyaviruses such as Rift Valley fever virus, and alphaviruses such as chikungunya virus. Sirtuin inhibitors block infection of these viruses in multiple human cell types. Moreover, we found that sirtuin inhibitors arrest infection downstream of entry but that they do so at an early step, preventing the accumulation of viral RNA and protein. Since these viruses infect vector insects, we also tested whether sirtuin inhibitors impacted infection of adult flies and found that these inhibitors blocked infection; therefore, they target highly conserved facets of replication. Taken together, these results suggest that sirtuin inhibitors represent a new class of potent host-targeting antivirals.
format	article
author	Brent A. Hackett Mark Dittmar Elisha Segrist Nathan Pittenger Julie To Trevor Griesman Beth Gordesky-Gold David C. Schultz Sara Cherry
author_facet	Brent A. Hackett Mark Dittmar Elisha Segrist Nathan Pittenger Julie To Trevor Griesman Beth Gordesky-Gold David C. Schultz Sara Cherry
author_sort	Brent A. Hackett
title	Sirtuin Inhibitors Are Broadly Antiviral against Arboviruses
title_short	Sirtuin Inhibitors Are Broadly Antiviral against Arboviruses
title_full	Sirtuin Inhibitors Are Broadly Antiviral against Arboviruses
title_fullStr	Sirtuin Inhibitors Are Broadly Antiviral against Arboviruses
title_full_unstemmed	Sirtuin Inhibitors Are Broadly Antiviral against Arboviruses
title_sort	sirtuin inhibitors are broadly antiviral against arboviruses
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/443ecdb4a429445e8eefee560540f5c9
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Sirtuin Inhibitors Are Broadly Antiviral against Arboviruses

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