CELL2FISH Interferon Regulatory Factor function 3/7 in fish – CELL2FISH

Interferon regulatory factors (IRF) 3 and 7 are critical transcription factors involved in the initial induction of type I interferon (IFN1), the main antiviral cytokine driving innate immunity against viral infections. Theirs mechanism of action is well described in mammalian models but appears to be different in fish. In particular, irf3 is an ISG in fish in contrast to human and salmonids have two irf7 paralogues, irf7-1 and irf7-2, which likely explains differences of IFN1 induction mechanisms. We recently isolated a salmonid cell line invalidated for both irf7 paralogs that exhibits a surprising constitutive IFN1 production associated with spontaneous resistance to a number of viruses. This led us to hypothesise that irf3/7 regulation pathways in fish are distinct from the canonical model described in mammals. While phylogenetic and expression analyses of irf3/7 have been reported in a number of fish species, the impact of these transcription factors on kinetics and efficiency of IFN1 responses against viruses remains unknown. To investigate this question, we will combine our cellular tools (in vitro k.o. cell lines) to in vivo models at the organism level using k.o. irf3/7 fish. These loss of function approaches will be developed in two fish families: cyprinids (irf3 and 7 ko zebrafish, irf3 and 7 ko fathead minnow cell lines) and salmonids (irf 7-1 and 7-2 ko rainbow trout, irf3 and 7 ko chinook salmon cell lines). The generation of cell lines and mutant animals with phenotypes either hypersensitive or resistant to virus infection will be evaluated for their potential commercial use in infectiology and/or in vaccinology. Four partners, two research units from INRAE (VIM, LPGP), one from CNRS/Pasteur Institute and a commercial company (VIRBAC) with complementary expertise will team up to deliver this project.