Viral infections are among the most frequent causes of human diseases and affect most people worldwide. While some viral diseases have been successfully combated, novel viral diseases like AIDS, SARS, avian influenza A H5N1, or the swine influenza A H1N1, have emerged over the last decades. Research aiming at elucidating mechanisms of viral infection and the involved immune response is, therefore, of utmost importance in order to understand viral pathogenesis and to identify novel potential drug targets. The goal of this proposal is to define the role of the RNA helicase DDX3X in the regulation of IFN-I expression. IFN-I is a central player of innate immunity and its secretion is rapidly induced upon stimulation of various receptors of the innate immune system, known as pattern recognition receptors. The current proposal aims at generating mice that lack functional DDX3X protein in specific tissues. We will test the ability of various cell types or DDX3X mutant mice to elicit effective IFN-I responses and we will assess the susceptibility to viral infections. Finally, we will examine the effect of DDX3X in acute lung injury, the main cause of death in individuals infected with SARS or influenza virus. These experiments are designed to reveal essential in vivo functions of a novel key molecule implicated in viral infections and therefore should contribute to the understanding and molecular consequences of the cellular host response to virus infections.