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Flu disease is an important public health burden worldwide, caused by the influenza virus that rapidly mutates and can cause severe disease and even death. While host genetic factors can also contribute to disease severity and susceptibility, no precise genetic determinant has been elucidated yet. Type-I IFNs, IFN-a/b, are hallmark molecules of the host innate immune responses, indispensable to the elimination of viruses. Previous work in our team directly correlated IFN-a/b levels in the lung to influenza susceptibility in a mouse model. Influenza-susceptible 129 mice exhibited higher IFN-a/b levels upon infection than resistant BL/6 mice, although all parameters of infection were similar. This PhD project was focused on uncovering the genetic determinants of excessive IFN-a/b production in mice. In this thesis, I present the impact of a novel candidate Chromosome 3 region in IFN-a/b responses: the R17 locus. A homozygous congenic BL/6 allele of the R17 locus contributed to reducing IFN-a/b and cytokine levels and to rescuing the susceptibility to influenza of the otherwise susceptible 129 mice. I report increased susceptibility in vivo and IFN-a/b production in vitro of BL/6 mice deficient in a candidate gene from the R17 locus, the a-protein kinase 1: ALPK1. Finally, this work reports some progress on elucidating the role of ALPK1 in IFN-a/b production pathways. By means of global phospho-proteome assays, a novel putative phosphorylation target of ALPK1, WWC2, is reported. This finding suggests a role for a previously unreported interaction between IFN-a/b responses and the Hippo pathway in innate immunity.