Emerging alphaviruses are sensitive to cellular states induced by a novel small-molecule agonist of the STING pathway

Bryan Gall, Kara Pryke, Jinu Abraham, Nobuyo Mizuno, Sara Botto, Tina M. Sali, Rebecca Broeckel, Nicole Haese, Aaron Nilsen, Andrew Placzek, Thomas Morrison, Mark Heise, Daniel Streblow, Victor De Filippis

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The type I interferon (IFN) system represents an essential innate immune response that renders cells resistant to virus growth via the molecular actions of IFNinduced effector proteins. IFN-mediated cellular states inhibit growth of numerous and diverse virus types, including those of known pathogenicity as well as potentially emerging agents. As such, targeted pharmacologic activation of the IFN response may represent a novel therapeutic strategy to prevent infection or spread of clinically impactful viruses. In light of this, we employed a high-throughput screen to identify small molecules capable of permeating the cell and of activating IFN-dependent signaling processes. Here we report the identification and characterization of N-(methylcarbamoyl)-2-([5-(4- methylphenyl)-1,3,4-oxadiazol-2-yl]sulfanyl)-2-phenylacetamide (referred to as C11), a novel compound capable of inducing IFN secretion from human cells. Using reverse geneticsbased loss-of-function assays, we show that C11 activates the type I IFN response in a manner that requires the adaptor protein STING but not the alternative adaptors MAVS and TRIF. Importantly, treatment of cells with C11 generated a cellular state that potently blocked replication of multiple emerging alphavirus types, including chikungunya, Ross River, Venezuelan equine encephalitis, Mayaro, and O'nyong-nyong viruses. The antiviral effects of C11 were subsequently abrogated in cells lacking STING or the type I IFN receptor, indicating that they are mediated, at least predominantly, by way of STING-mediated IFN secretion and subsequent autocrine/paracrine signaling. This work also allowed characterization of differential antiviral roles of innate immune signaling adaptors and IFN-mediated responses and identified MAVS as being crucial to cellular resistance to alphavirus infection.

Original languageEnglish (US)
Article numbere01913-17
JournalJournal of Virology
Volume92
Issue number6
DOIs
StatePublished - Mar 1 2018

Fingerprint

Alphavirus
interferons
Interferons
agonists
Interferon Type I
Viruses
O'nyong-nyong Virus
Antiviral Agents
Alphavirus Infections
Venezuelan Equine Encephalomyelitides
Autocrine Communication
Interferon alpha-beta Receptor
Paracrine Communication
O'nyong-nyong virus
viruses
cells
Growth
Innate Immunity
Rivers
secretion

Keywords

  • Alphavirus
  • Antiviral agents
  • Chikungunya virus
  • Interferon
  • IRF3
  • Mayaro virus
  • O'nyong-nyong virus
  • Ross River virus
  • STING
  • Venezuelan equine encephalitis virus

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Gall, B., Pryke, K., Abraham, J., Mizuno, N., Botto, S., Sali, T. M., ... De Filippis, V. (2018). Emerging alphaviruses are sensitive to cellular states induced by a novel small-molecule agonist of the STING pathway. Journal of Virology, 92(6), [e01913-17]. https://doi.org/10.1128/JVI.01913-17

Emerging alphaviruses are sensitive to cellular states induced by a novel small-molecule agonist of the STING pathway. / Gall, Bryan; Pryke, Kara; Abraham, Jinu; Mizuno, Nobuyo; Botto, Sara; Sali, Tina M.; Broeckel, Rebecca; Haese, Nicole; Nilsen, Aaron; Placzek, Andrew; Morrison, Thomas; Heise, Mark; Streblow, Daniel; De Filippis, Victor.

In: Journal of Virology, Vol. 92, No. 6, e01913-17, 01.03.2018.

Research output: Contribution to journalArticle

Gall, B, Pryke, K, Abraham, J, Mizuno, N, Botto, S, Sali, TM, Broeckel, R, Haese, N, Nilsen, A, Placzek, A, Morrison, T, Heise, M, Streblow, D & De Filippis, V 2018, 'Emerging alphaviruses are sensitive to cellular states induced by a novel small-molecule agonist of the STING pathway', Journal of Virology, vol. 92, no. 6, e01913-17. https://doi.org/10.1128/JVI.01913-17
Gall, Bryan ; Pryke, Kara ; Abraham, Jinu ; Mizuno, Nobuyo ; Botto, Sara ; Sali, Tina M. ; Broeckel, Rebecca ; Haese, Nicole ; Nilsen, Aaron ; Placzek, Andrew ; Morrison, Thomas ; Heise, Mark ; Streblow, Daniel ; De Filippis, Victor. / Emerging alphaviruses are sensitive to cellular states induced by a novel small-molecule agonist of the STING pathway. In: Journal of Virology. 2018 ; Vol. 92, No. 6.
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AU - Sali, Tina M.

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AU - Haese, Nicole

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