Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway

• DOI: 10.1128/jvi.02202-15
• Publication Date: 2015-12-17T03:58:16Z
• Authors: Sowmya Pattabhi; Courtney R. Wilkins; Ran Dong; Megan L. Knoll; Jeffrey Posakony; Shari Kaiser; Chad E. Mire; Myra L. Wang; Renee C. Ireton; Thomas W. Geisbert; Kristin M. Bedard; Shawn P. Iadonato; Yueh-Ming Loo; Michael Gale
• Keywords: IRF3; RIG-I; Filoviridae; RNA virus

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 3 (IRF3). IRF3 plays a critical role antiviral immunity drive expression innate immune genes, including those encoding factors, type 1 interferon, and modulatory cytokines, act concert restrict replication. Thus, small molecule agonists can promote activation induce gene could serve as antivirals tissue-wide for effective control infection. We identified compounds differentially discrete subsets genes. tested lead compound derivatives ability suppress infections caused by broad range RNA viruses. Compound administration significantly decreased load cultured cells were infected with viruses family Flaviviridae , West Nile virus, dengue hepatitis C well families Filoviridae (Ebola virus), Orthomyxoviridae (influenza A Arenaviridae (Lassa Paramyxoviridae (respiratory syncytial Nipah virus) infectious production. Knockdown studies mapped this RIG-I-like receptor pathway. work identifies novel class host-directed molecules host responses broadly distinct genera. IMPORTANCE Incidences emerging reemerging highlight desperate need broad-spectrum agents effectively selectively purpose identifying drug-like be developed treatment infections. Here, we report discovery hydroxyquinoline responses. These prophylactically or therapeutically cell culture pathogenic viruses, influenza respiratory Lassa Ebola virus. Our study thus mechanism enhance activity against variety pose significant health care burden and/or are known cause high case fatality rates.