A network-informed analysis of SARS-CoV-2 and hemophagocytic lymphohistiocytosis genes' interactions points to Neutrophil extracellular traps as mediators of thrombosis in COVID-19

Author summary In this manuscript we mined available genetic information on a life-threatening disease associated with hyperinflammation, hemophagocytic lymphohistiocytosis (HLH), that shares similarities with features of severe COVID-19 to identify potential molecular mechanisms of pathogenesis. This was achieved using advanced computational algorithms that generated a network of interactions linking the host gene products to the viral proteins of SARS-CoV-2, responsible for COVID-19. The information contained within the interaction network was then exploited by a different set of computer algorithms to 1) identify an inflammatory process, the release of extracellular traps from neutrophils, circulating immune cells involve in host defence, as a potential mechanism increasing the risk of abnormal coagulation in severe COVID-19 and 2) predict potential underlying conditions or co-morbidities that increases the risk of severe COVID-19. Therefore, we hypothesize that inflammatory conditions that predispose neutrophils to release extracellular traps may enhanced the likelihood of developing coagulation problems that have may have serious consequences for COVID-19 clinical trajectory. Abnormal coagulation and an increased risk of thrombosis are features of severe COVID-19, with parallels proposed with hemophagocytic lymphohistiocytosis (HLH), a life-threating condition associated with hyperinflammation. The presence of HLH was described in severely ill patients during the H1N1 influenza epidemic, presenting with pulmonary vascular thrombosis. We tested the hypothesis that genes causing primary HLH regulate pathways linking pulmonary thromboembolism to the presence of SARS-CoV-2 using novel network-informed computational algorithms. This approach led to the identification of Neutrophils Extracellular Traps (NETs) as plausible mediators of vascular thrombosis in severe COVID-19 in children and adults. Taken together, the network-informed analysis led us to propose the following model: the release of NETs in response to inflammatory signals acting in concert with SARS-CoV-2 damage the endothelium and direct platelet-activation promoting abnormal coagulation leading to serious complications of COVID-19. The underlying hypothesis is that genetic and/or environmental conditions that favor the release of NETs may predispose individuals to thrombotic complications of COVID-19 due to an increase risk of abnormal coagulation. This would be a common pathogenic mechanism in conditions including autoimmune/infectious diseases, hematologic and metabolic disorders.