Targeting innate immunity for antiviral therapy through small molecule agonists of the RLR pathway

Sowmya Pattabhi, Courtney R. Wilkins, Ran Dong, Megan L. Knoll, Jeffrey Posakony, Shari Kaiser, Chad Mire, Myra L. Wang, Renee C. Ireton, Thomas Geisbert, Kristin M. Bedard, Shawn P. Iadonato, Yueh Ming Loo, Michael Gale

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The cellular response to virus infection is initiated when pathogen recognition receptors (PRR) engage viral pathogen-associated molecular patterns (PAMPs). This process results in induction of downstream signaling pathways that activate the transcription factor interferon regulatory factor 3 (IRF3). IRF3 plays a critical role in antiviral immunity to drive the expression of innate immune response genes, including those encoding antiviral factors, type 1 interferon, and immune modulatory cytokines, that act in concert to restrict virus replication. Thus, small molecule agonists that can promote IRF3 activation and induce innate immune gene expression could serve as antivirals to induce tissue-wide innate immunity for effective control of virus infection. We identified small molecule compounds that activate IRF3 to differentially induce discrete subsets of antiviral genes. We tested a lead compound and derivatives for the ability to suppress infections caused by a broad range of RNA viruses. Compound administration significantly decreased the viral RNA load in cultured cells that were infected with viruses of the family Flaviviridae, including West Nile virus, dengue virus, and hepatitis C virus, as well as viruses of the families Filoviridae (Ebola virus), Orthomyxoviridae (influenza A virus), Arenaviridae (Lassa virus), and Paramyxoviridae (respiratory syncytial virus, Nipah virus) to suppress infectious virus production. Knockdown studies mapped this response to the RIG-I-like receptor pathway. This work identifies a novel class of host-directed immune modulatory molecules that activate IRF3 to promote host antiviral responses to broadly suppress infections caused by RNA viruses of distinct genera.

Original languageEnglish (US)
Pages (from-to)2372-2387
Number of pages16
JournalJournal of Virology
Volume90
Issue number5
DOIs
StatePublished - 2016

Fingerprint

Interferon Regulatory Factor-3
Innate Immunity
agonists
Antiviral Agents
viruses
therapeutics
Virus Diseases
Viruses
Filoviridae
Arenaviridae
RNA Virus Infections
infection
Lassa virus
Paramyxoviridae
Nipah Virus
Flaviviridae
Ebolavirus
Therapeutics
Nipah virus
West Nile virus

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Pattabhi, S., Wilkins, C. R., Dong, R., Knoll, M. L., Posakony, J., Kaiser, S., ... Gale, M. (2016). Targeting innate immunity for antiviral therapy through small molecule agonists of the RLR pathway. Journal of Virology, 90(5), 2372-2387. https://doi.org/10.1128/JVI.02202-15

Targeting innate immunity for antiviral therapy through small molecule agonists of the RLR pathway. / Pattabhi, Sowmya; Wilkins, Courtney R.; Dong, Ran; Knoll, Megan L.; Posakony, Jeffrey; Kaiser, Shari; Mire, Chad; Wang, Myra L.; Ireton, Renee C.; Geisbert, Thomas; Bedard, Kristin M.; Iadonato, Shawn P.; Loo, Yueh Ming; Gale, Michael.

In: Journal of Virology, Vol. 90, No. 5, 2016, p. 2372-2387.

Research output: Contribution to journalArticle

Pattabhi, S, Wilkins, CR, Dong, R, Knoll, ML, Posakony, J, Kaiser, S, Mire, C, Wang, ML, Ireton, RC, Geisbert, T, Bedard, KM, Iadonato, SP, Loo, YM & Gale, M 2016, 'Targeting innate immunity for antiviral therapy through small molecule agonists of the RLR pathway', Journal of Virology, vol. 90, no. 5, pp. 2372-2387. https://doi.org/10.1128/JVI.02202-15
Pattabhi, Sowmya ; Wilkins, Courtney R. ; Dong, Ran ; Knoll, Megan L. ; Posakony, Jeffrey ; Kaiser, Shari ; Mire, Chad ; Wang, Myra L. ; Ireton, Renee C. ; Geisbert, Thomas ; Bedard, Kristin M. ; Iadonato, Shawn P. ; Loo, Yueh Ming ; Gale, Michael. / Targeting innate immunity for antiviral therapy through small molecule agonists of the RLR pathway. In: Journal of Virology. 2016 ; Vol. 90, No. 5. pp. 2372-2387.
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