170 : Targeting RIG-I-like receptor signaling and innate immunity for adjuvant activity

Abstract

RIG-I-like receptors (RLR) are cytoplasmic pathogen recognition receptors that detect pathogen-associated molecular patterns (PAMP) within viral RNA and initiate the innate antiviral immune response that is essential for controlling many RNA virus infections. Viral PAMP engagement of RLR initiates a signaling cascade and transcriptional program that culminates in the expression of antiviral genes that restrict virus replication and spread and induces the secretion of cytokines and chemokines that support the development of adaptive immunity. We hypothesize that agonists that activate RLR signaling pathways will induce innate and adaptive immune responses that can be used to enhance vaccine protection to RNA virus infections. Using a high throughput cell-based screening approach, we have now identified drug-like compounds that target the RLR pathway and drive IRF-3 activation. We found that these compounds differentially induce proinflammatory cytokine and chemokine production, and the expression of antiviral and antigen presentation genes in treated cells. On their own, the compounds exhibit varying efficacy in limiting RNA virus infections. Moreover, the compounds promote dendritic cell maturation and enhance antigen-dependent activation of effector T cell function. Importantly, when paired with a vaccine at suboptimal dose, the compounds elicited an immune response that protected mice from lethal influenza virus challenge. The compounds also elicited an immune response to suboptimal doses of an experimental West Nile virus vaccine that protected mice from virus infection. Our study thus identifies novel immune-modulating molecules that function as innate immune agonists of RLR signaling to enhance vaccine-induced immunity. Our analyses reveal the strong potential of developing these RLR agonists as a new class of adjuvants for RNA virus vaccines. Our study demonstrates that targeting RLR signaling for innate immune induction is a viable approach for new immune therapies.