Innate Immunity

Virus-host interactions are characterized by a remarkable sequence of “one-upmanship” responses that alternately tip the advantage between the pathogen and the infected cell. Among host responses, viral RNA molecules are recognized as foreign invaders by cytoplasmic RNA helicase receptors that serve as innate immune signaling molecules. Innate immune responses occur very early after infection, and precede the adaptive immune responses that generate antibodies. The RNA helicase receptors (called RIG-I and MDA5) act independently of the toll-like receptor (TLR) pathways to stimulate interferon expression, creating an anti-viral state.

We have found that pathogenic viral RNAs are not equal in terms of their abilities to activate innate immune signaling. Specifically, our data indicate that the 5′ and 3′ untranslated regions of dengue virus and West Nile virus RNAs are comparatively weak activators in comparison with the 3′ untranslated region of hepatitis C virus. The goal of our work is to identify RNA sequence and structural features that activate innate immune signaling through the cytoplasmic RNA helicases RIG-I and MDA-5.

Graduate student Dina Uzri has identified a small (100 nucleotide) region in the 3′ untranslated region of the hepatitis C virus RNA that is responsible for potent activation of innate immune signaling. However, if the uridine bases in this RNA are substituted with pseudouridine or other modified nucleotides, signaling to interferon expression is blocked, but the RNAs continue to bind RIG-I. This finding provides us with a tool to dissect the activation pathways.

Current work is directed at understanding how the activating sequence contributes to both replication and innate immune signaling in the context of HCV replicon RNAs. In collaboration with the laboratories of Sangeeta Bhatia (MIT), and Dan Anderson (MIT), we are testing the delivery of immunomodulatory RNAs into primary human cells.