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The role of complement in SARS-CoV-2-triggered thrombosis
COVID-19 Research Area(s): Diagnostics, Genomics & Transmission Dynamics, Vaccines & Treatments
Patients with COVID-19 most often suffer from breathing problems, but they also have a high risk of developing dangerous blood clots (thrombosis) in their blood vessels. Indeed, it is the widespread excess clotting of blood that likely causes most of the morbidity and mortality associated with COVID-19. The increased risk of thrombosis in COVID-19 is not well understood, and treatment with traditional anti-clotting drugs (anticoagulants) works only to a limited extent. Therefore, we need to better understand why COVID-19 patients develop the clots so that we can develop/use more effective medicines. Based on recent work, we know that a part of the immune system in the blood, referred to as complement, is over-activated in patients with COVID-19. When over-activated, complement components (there are several) cause the blood clotting system (coagulation) to also become over-activated, increasing the risk of thrombosis. In line with a link between these systems, anti-complement drugs have been used in other diseases to effectively prevent thrombosis. If we confirm a link between complement over-activation and thrombosis in COVID-19, anti-complement drugs could be rapidly evaluated in clinical trials.
Problem: The most dreaded outcomes from COVID-19 occur when rapid and catastrophic tissue damage involves multiple organs that is linked often to widespread vascular thrombosis. The pathophysiological mechanisms underlying this dramatic host response to SARS-CoV-2 are largely unexplained. Such information would yield urgently needed diagnostic and therapeutic strategies.
Background: Studies with SARS-CoV-2 and the related pathogenic coronaviruses, SARS-CoV and MERS-CoV, support the notion that complement activation participates in the virus-related organ damage and thrombosis and that complement hyper-activation correlates directly with disease severity. Knowledge of the relationship of complement activation with COVID-19 severity, of the complement pathways involved and the molecular mechanisms by which SARS-CoV-2 mediates complement activation and thrombosis, would lead to the rational design of novel anti-complement therapeutic agents.
Hypothesis: Complement plays a key role in the pathogenesis of SARS-CoV-2-mediated tissue injury and thrombosis. Identifying the molecular mechanisms will yield insights for the rapid development of novel diagnostics and effective therapies. Specific Aims 1. To elucidate the relationship between complement activation and COVID-19 associated multi-organ damage and thrombosis in hospitalized patients during the course of their disease. We are serially measuring complement activation in the blood of COVID-19 adult patients and corresponding COVID-19-negative controls admitted to UBC hospitals during their hospital stays. Activation products of the complement and coagulation cascades are being quantified, the results of which are informing on the pathway(s) involved. 2. To delineate the mechanisms by which complement and coagulation are modulated by proteins encoded by SARS-CoV-2. We predict that one or more of these alter the structure and/or function of complement components or complexes that result in a net excess in complement and coagulation activation. Recombinant forms of proproteins encoded by SARS-CoV-2 are being screened for effects on complement activation and coagulation. Established solution phase and cell-based assays are being utilized, and candidate proteins are being further evaluated by physicochemical approaches to elucidate molecular interactions and mechanisms. Summary: We are rapidly gaining unique insights into the molecular mechanisms by which SARS-CoV-2 infection enhances complement and coagulation activation via interactions with specific proteins. Biomarkers of predictive value have already been identified, while key pathways involved are yielding insights that will lead to rational interventional strategies that will hopefully help to mitigate the organ damage associated with COVID-19.Collaboration opportunities:
1. Assess the effects of potential therapeutic compounds on complement/coagulation. 2. Genetics studies of COVID-19 patients to evaluate whether alterations in genes encoding complement/coagulation affect outcome/risk.