Grant: Operating Grant

The innate immune system is the first line of defense against pathogens and relies on the recognition of molecular structures specific to pathogens by sensor receptors. These receptors activate a signaling cascade to induce a protective cellular response involving expression of pro-inflammatory and antiviral cytokines (including interferon beta) and chemokines. The production of type I interferon optimizes the innate response of infected and surrounding cells by activation of the transcription factor complex known as ISGF3 for induction of a large number of IFN-stimulated genes (ISGs). The tight regulation of such optimal innate response is important to ensure viral clearance, while preventing excessive inflammation. This research program aims at developing broad spectrum therapies for infectious diseases based on novel biology exploiting regulators of innate immunity. We used loss-of-function RNA interference screen to individually impair the expression of every gene in the human genome. Such approach leads to an unprecedented knowledge regarding identification of hundred potential modulators of the tightly regulated interferon beta cytokine critical in the control of acute infection. Modulator hits uncovered by the screens encoded druggable protein targets based on shared biological functions namely secreted proteins, spliceosome proteins, proteasome proteins, ion transport proteins and nucleocytoplasmic transport proteins. Our study revealed novel immunoregulatory roles of a canonical-like WNT/beta-catenin pathway and of the spliceosome in the regulation of virus-mediated innate response. In this proposal, we plan to decipher the mechanistic involvement of novel innate immune regulators and their effects on various viral infections, to expand our observations to in vivo models using knockout mice and to to identify new immunomodulatory compounds for the treatment of broad-spectrum virus infections or to limit virus-induced immune disorders.