Leveraging Systems Biology To Target Hyperinflammation In Critically-ill Covid-19 Patients

The emergence of COVID-19 pandemic implies new challenges for the Health Systems worldwide. A small percentage of the patients require hospitalisation and specialised attention in Intensive Care Units (ICUs). Furthermore, accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. Therefore, the main goal of the proposal is to elucidate the potential role of cytokine storm in COVID-19 disease severity, and to propose novel strategies for counteracting this hyperinflammatory response. In this context, we propose to develop a single-cell based systems biology approach that infers and compares functional cell-cell communication networks of immune cells between patients with mild and severe symptoms to characterize the cytokine storm and, in particular, to identify functionally relevant intercellular positive feedback loops maintaining this hyperinflammatory condition. Indeed, feedback loops have been shown to support the inflammatory response in other infectious diseases. Therefore, we propose that these loops are responsible for maintaining and amplifying the cytokine storm during the COVID-19 infection. As a plausible therapeutic strategy to modulate hyperinflammation, we propose to target these feedback loops by simulating the effect of perturbing receptor-ligand interactions as well as intracellular signaling molecules participating in them. In this regard, an automatic search in databases of clinically approved drugs would identify candidates for specifically disrupting or modulating the functioning of these loops. To carry out this study we will perform a single cell RNA sequencing of blood cells from 16 COVID-19 patients, half of which only showing mild symptoms whereas the others present with severe symptoms needing ICU treatment.