RIG-ging the host innate immune response for vaccine adjuvant and antiviral therapy

Abstract

Abstract Retinoic acid inducible gene I (RIG-I) is essential for directing and priming the host immune response against many RNA viruses. A diverse small molecule library was used in a cell-based screening approach to identify drug-like compounds that could target the RIG-I signaling pathway and induce downstream IRF3 to drive innate antiviral immunity. We identified small molecule compounds that activate IRF3 to induce discrete subsets of innate immune and antiviral genes. We identified a class of hydroxyquinoline compounds that induce IRF3 activation and innate immunity of cultured cells to decrease viral RNA load and infectious virus production, thereby controlling infection by viruses of the families Flaviviridae, Filoviridae, Orthomyxoviridae, Arenaviridae and Paramyxoviridae. In addition, we identified a second class of benzo-bisthiazole compounds that directly engage and activate RIG-I to promote downstream IRF3 signaling and the expression of innate immune genes, cytokines and chemokines. Importantly, these compounds serve potent immune adjuvant functions to promote the maturation of dendritic cells to enhance antigen presentation and T cell activation. When administered to mice in combination with influenza A virus or West Nile virus vaccine, this compound conferred adjuvant activity to facilitate vaccine-mediated protection of mice from lethal virus challenge under conditions of otherwise suboptimal vaccine dose. Thus, we have identified novel small molecule RIG-I agonists that activate the innate immune response. Our studies reveal the strong potential of developing small molecule RIG-I agonists as broad-spectrum antiviral agents to control RNA virus infection and as adjuvants to potentiate vaccine immunity.