Project Details
Projekt
Profiling anti-influenza activities of the pathogen recognition receptor RIG-I: Novel targets for antiviral intervention strategies
Subject Area
Clinical Infectiology and Tropical Medicine
Term
from 2016 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 284237345
RIG-I is a cellular virus sensor that binds the 5’ppp-dsRNA panhandle of Influenza A virus (FLUAV). RIG-I then switches conformation and can exert a direct antiviral effect by clamping onto the panhandle and disassembling the polymerase complex, but normally it also triggers antiviral signaling leading to type I interferon (IFN) production. We had generated mutants of RIG-I that reduce viral RNA synthesis despite being deficient in antiviral signaling. The antiviral mechanism of these RIG-I mutants will be explored and optimized by defining the minimally required domain and by further modifications. We already have created mice bearing one such RIG-I mutant (K271A), and will compare their FLUAV resistance with wt and RIG-I KO mice. Paliperidone, an FDA-approved antipsychotic predicted by Patel & Kukol (Virology 2017) to bind PB2, was shown to mimic the direct antiviral activity of RIG-I as it diminished the binding of PB2 to nucleocapsids and reduced RNA synthesis of the PR8/34 strain. We will test Paliperidone against a variety of FLUAV strains in cell lines and primary human airway cells, investigate a potential involvement of RIG-I in its antiviral effect, and evaluate its interplay with RIG-I agonists. Also, we identified rRNA-derived self-RNA fragments as new RIG-I ligands. These RIG-I stimulators can be generated by the OAS/ RNase L that in turn can be activated by dsRNA and the glycolysis intermediate Fructose-1,6-bisphosphate (F16bP). This possible link between an endogenous intermediate of glycolysis and innate immunity will be followed up in OAS/RNase L knockout cells. Moreover, the influence of the metabolic state of macrophages on RNase L activation, self-RNA fragment generation and subsequent RIG-I-mediated antiviral activity will be investigated.
DFG Programme
Clinical Research Units
