Two years into the COVID-19 pandemic, SARS-CoV-2 infections are still responsible for huge economic losses, lockdowns and stressed health care systems worldwide. Different from the situation early during the pandemic, when the virus started circulating in the human population in the absence of pre-existing immunity, SARS-CoV-2-specific immunity has been increased at the community level due to vaccination or previous infection. Nevertheless, through the acquisition of mutations, new variants of the virus emerged that were able to escape pre-existing immunity and to transmit with higher efficiency, thereby causing a continuous threat for severe disease, especially in people with comorbidities like obesity, advanced age and associated morbidities like type 2 diabetes and hypertension. In Project 1, we will identify key drivers and biomarkers for severe disease networks associated with SARS-CoV-2 infection through modeling, based on multi-OMICs data obtained from clinical and animal studies. Under AIM 1, a first dataset will be generated from clinical samples of COVID-19 patients in the absence or presence of pre-existing immunity. Multi-OMICs data will also be generated using established animal models (mouse and hamster) for SARS-CoV-2 infection to recapitulate clinical characteristics and features from the human cohort studies, thereby taking advantage of our expertise with animal models for specific comorbidities (obesity, type 2 diabetes, advanced age) while always addressing sex and immune status as a biological variables. Both human and animal datasets will be used by the modeling core under AIM 2 to identify networks associated with severe and mild disease outcome, and the host and virus genes that drive them. Under AIM 3, networks and signature genes identified under AIM 2 will be validated in vivo using the mouse and hamster infection models for SARS-CoV-1. Hereto, we will rely on the availability of knock out mice, viral vector-mediated genetic ablation of host genes in cells licensed for SARS- CoV infection, when available pharmacological interventions, recombinant rSARS-CoV-1 and rSARS-CoV-2 viruses and SARS-CoV-2 variants that have acquired mutations in genes of interest by nature. The overarching goal of our highly integrated research strategy is to uncover molecular signatures associated with distinct disease trajectories and outcomes, identifying novel targets for therapeutic interventions.