You are here

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

Targeting innate immunity for antiviral therapy through small molecule agonists of the RLR pathway.
Author: 
Michael Gale Jr., Ph.D.
Published: 
Dec 2015
Publisher: 
16 December 2015, doi: 10.1128/JVI.02202-15

Pattabhi S1, Wilkins CR2, Dong R1, Knoll ML2, Posakony J3, Kaiser S3, Mire CE4, Wang ML3, Ireton RC2, Geisbert TW4, Bedard KM3, Iadonato SP5, Loo YM6, Gale M Jr7.

Author information

  • 1Departments of Global Health and and Immunology the Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA.
  • 2Departments of Global Health and and Immunology the Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA Departments of Global Health and and Immunology the Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA.
  • 3KINETA Inc., Seattle, Washington, USA.
  • 4University of Texas Medical Branch at Galveston, Galveston National Laboratory, Galveston, Texas, USA.
  • 5Departments of Global Health and and Immunology the Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA KINETA Inc., Seattle, Washington, USA.
  • 6Departments of Global Health and and Immunology the Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA Departments of Global Health and and Immunology the Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA mgale@uw.edu looy@uw.edu.
  • 7Departments of Global Health and and Immunology the Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA Departments of Global Health and and Immunology the Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA Departments of Global Health and and Immunology the Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA mgale@uw.edu looy@uw.edu.

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 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 infection by a broad range of RNA viruses. Compound administration significantly decreased the viral RNA load in cultured cells that were infected with 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 infection by RNA viruses of distinct genera.

IMPORTANCE:

Incidences of emerging and re-emerging RNA viruses highlight a desperate need for broad-spectrum antiviral agents that can effectively control infection by viruses of distinct genera. We identified small molecule compounds that can selectively activate IRF3 for the purpose of identifying drug-like molecules that can be developed for the treatment of viral infections. Here, we report the discovery of a hydroxyquinoline family of small molecules that can activate IRF3 to promote cellular antiviral responses. These molecules can prophylactically or therapeutically control infection in cell culture by pathogenic RNA viruses including West Nile virus, dengue virus, hepatitis C virus, influenza A virus, respiratory syncytial virus, Nipah virus, Lassa virus and Ebola virus. Our study thus identifies a class of small molecules with novel mechanism to enhance host immune responses for antiviral activity against a variety of RNA viruses that pose a significant healthcare burden and/or with known high case fatality rates.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

PMID:26676770