Influenza A virus is an important human pathogen that causes respiratory disease of different grades of severity according to the specific virus strain and to host susceptibility. Our underlying main hypothesis is that host genes and networks involved in viral replication and in early host responses regulate disease outcome and represent promising targets for therapeutic intervention. We also propose that there are multiple distinct pathways that result in either resilience or pathogenic outcomes after influenza virus infection, and that different pathogenic pathways will require different therapeutic interventions. We are proposing an integrated systems level approach to discover and characterize the critical networks involved in influenza virus pathogenesis, their associated biomarkers, and key drivers of these signatures that can be targeted for therapeutic intervention.
Our program is a logical extension of our previous consortium entitled “Multiscale analysis of influenza host-pathogen interactions: FluOMICS”. During our original FluOMICS program we successfully characterized the impact of influenza virus infection on the global epigenome, transcriptome, proteome and metabolome in primary relevant human cells and in mouse lungs after infection with three different influenza viruses with defined and distinct degrees of virulence. In “FluOMICS, the NEXT Generation,” we will leverage these global datasets and models generated by us that predict severity of disease caused by these viruses. These results represent critical benchmarks for comparison with multiple specific perturbations in virus, host, and environmental factors, resulting in enhanced or decreased disease and/or replication in our ex vivo and mouse models. Using our established system biology approaches combined with leading edge technologies, such as Pertub/Seq and CRISPR/OMICS, we will refine our existing models and unravel additional pathogenic and resilient networks that drive the outcome of influenza virus infection. Importantly, we have added to our NEXT Generation proposal a clinical component in which such networks are also identified in blood of a clinically defined cohort of patients infected with influenza viruses. Specifically, our modeling approaches will find correlates between experimental systems that will help us define human blood biomarkers and link them to in vivo and ex vivo signatures for both companion diagnostics and personalized therapies.