Department of Veterinary and Biomedical Sciences
Liang/Ly Lab Manuscript is Published in JVI
This paper discusses the development of novel antiviral treatments and/or vaccines against some arenaviruses that can cause severe and lethal hemorrhagic fever diseases in humans.
RIG-I is a major cytoplasmic sensor of viral pathogen-associated molecular pattern (PAMP) RNA and induces the production of type I interferon (IFN) upon viral infection. A dsRNA-binding protein PACT plays an important role in potentiating RIG-I function. We have previously shown that arenaviral nucleoproteins (NPs) suppress type I IFN production via its exoribonuclease (RNase) activity to degrade PAMP RNA. We report here that NPs of arenaviruses block PACT-induced enhancement of RIG-I function to mediate type I IFN production and that the inhibition is dependent on the NP's RNase function, which is different than a known mechanism of other viral proteins to disrupt PACT and RIG-I interaction. To understand the biological roles of PACT and RIG-I in authentic arenavirus infection, we analyze growth kinetics of recombinant Pichinde virus (PICV), a prototypic arenavirus, in RIG-I knock-out (KO) and PACT KO mouse embryonic (MEF) cells. WT PICV grew at higher titers in both KO MEF lines than in normal MEFs, suggesting the important roles of these cellular proteins in restricting virus replication. PICV carrying the NP RNase catalytically inactive mutation could not grow in normal MEFs but could replicate to some extent in both KO MEF lines. The level of viral growth inversely correlated with the amount of type I IFNs produced. These results suggest that PACT plays an important role in potentiating RIG-I function to induce type I IFNs in order to restrict arenavirus replication, and that viral NP RNase activity is essential for optimal viral replication by suppressing PACT-induced RIG-I activation.