Devils dance: complement, NETs and thrombosis in COVID-19

Corona virus disease 2019 (COVID-19) presents with flu-like symptoms and viral pneumonia, which may progress to acute respiratory distress syndrome (ARDS) and occasionally to multiple organ dysfunction syndrome (MODS). Cardiovascular complications in the form of arterial and venous thrombosis contribute to ARDS, MODS and fatality. So far, there is no effective therapy for COVID-19. There is evidence that an overwhelming host response of the innate immunity contributes to the development of ARDS and vascular complications. Preliminary data suggest a role of complement and neutrophil activation in the form of neutrophil extracellular traps (NETs) in this response. The aim of the proposal is to identify complement activation (including the specific pathways involved) with subsequent neutrophil activation in the form of NETs to be the main drivers for the development of ARDS and microvascular complications in COVID-19. The results will form the base to establish and implement timely therapies targeting complement- and neutrophil activation in order to prevent and/or treat ARDS and microvascular complications in COVID-19 patients. The methodology applied in this project relies on the applicant's expertise in complement and neutrophil biology to measure and subsequently dissect complement- and neutrophil activation pathways in COVID-19. The obtained biochemical results will be related to clinical data of COVID-19 patients included in this study. The planned analysis will also include testing for genetic susceptibility potentially predisposing for an overwhelming host response to SARS-CoV-2, as evidenced by an excessive complement activation and NET formation. Finally, we will identify the contribution of complement and NETs in hypercoagulability using assays to follow coagulation in real-time. All the assays and techniques described in the current proposal are operational. We expect to establish surrogate markers in this innate host immune response in order to identify either patients at risk for complications (e.g. ARDS, microvascular complications) and/or patients suitable for a therapy targeting complement and/or neutrophils. The current application is embedded in a strong national and international complementary scientific network enabling a) access to blood samples and clinical data from COVID-19 patients treated at different University Hospitals in Switzerland; b) access to national and international specialized infrastructures and laboratory techniques, e.g. genetic platforms (collaboration with the University Hospital Geneva) and assays for complement activation (Sanquin Research, Amsterdam, the Netherlands); and c) participation in intervention studies targeting complement (University Hospital Basel). This strong scientific network is a prerequisite to accomplish the proposed project successfully in time. The results of the current proposal will provide the molecular mechanisms of complement activation with subsequent neutrophil activation and establish their significant role in the pathogenesis of hypercoagulability in COVID-19. The current study will identify the level and the pathway on which complement - and neutrophil inhibition will be most effective and hence will form the base to introduce therapies targeting either complement- or/and neutrophil activation. Especially in the complement field, there is a plethora of new inhibitors emerging targeting different complement pathways at different levels, but only a few are tested in clinical studies or are available for other indications than COVID-19. The results of current application will contribute to accelerate clinical testing and implementation of candidate drugs targeting complement providing a rational and effective therapeutic strategy to treat COVID-19.