Funded by the National Institute of Allergy and Infectious Diseases, we have reassembled our highly diverse team of investigators from throughout the US that worked on the original FluOMICS (fluomics.org) project, plus two additional investigators (one international), to continue our systematic approaches to generating predictive models of influenza virus pathogenesis. The proposed studies leverage our previous collaborations that generated global datasets and models that predict severity of disease caused by three influenza virus strains with different levels of virulence. The overarching theme of our multidisciplinary proposal “FluOMICS: The NEXT Generation” is to obtain multiple OMICS-based systems level measurements and integrate them using modeling approaches and machine learning algorithms to identify and validate 1) host-virus networks that modulate influenza A virus disease severity, 2) biomarkers in blood that reflect the activation states of these networks and 3) novel host targets for therapeutic interventions.