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Complement contributions to COVID-19
Edward M Conway1,2,3, Edward L G Pryzdial1,4,5,3
1Centre for Blood Research, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Insights
The complement system, a key part of innate immunity, is dysregulated in COVID-19, driving organ damage through thromboinflammation and vascular endotheliopathy. Understanding these interactions reveals new therapeutic targets for SARS-CoV-2 infection.
Area of Science:
- Immunology
- Infectious Diseases
- Vascular Biology
Background:
- COVID-19 causes organ damage and vascular endotheliopathy, with long-term effects and emerging variants posing ongoing concerns.
- The precise mechanisms of SARS-CoV-2-induced organ damage and vascular dysfunction are not fully understood, impeding drug development.
- The complement system, a crucial component of innate immunity, is known to be dysregulated in COVID-19 patients.
Purpose of the Study:
- To elucidate the role of the complement system in the thromboinflammatory response and vascular endotheliopathy associated with SARS-CoV-2 infection.
- To highlight key interactions between the complement system and other innate immune pathways in COVID-19 pathogenesis.
- To identify potential therapeutic targets for mitigating COVID-19-related organ damage.
Main Methods:
- Review of recent studies on complement activation by SARS-CoV-2.
- Analysis of the interplay between complement and other thromboinflammatory pathways (platelets, neutrophils, NETs, coagulation, kallikrein-kinin systems).
- Delineation of molecular and cellular mechanisms driving endotheliopathy and organ damage.
Main Results:
- SARS-CoV-2 directly activates the complement system.
- Complement activation interfaces with platelet, neutrophil, and coagulation pathways, contributing to thromboinflammation.
- The complement system plays a prominent role in promoting endotheliopathy and organ damage, directly and through interactions with other systems.
Conclusions:
- The complement system is a central player in SARS-CoV-2-mediated thromboinflammation and vascular endotheliopathy.
- Understanding complement's intricate interactions with other pathways offers promising strategies for therapeutic intervention.
- Targeting the complement system presents a potential avenue for novel drug development against COVID-19 and its complications.
Purpose Of Review:
COVID-19 remains a major source of concern, particularly as new variants emerge and with recognition that patients may suffer long-term effects. Mechanisms underlying SARS-CoV-2 mediated organ damage and the associated vascular endotheliopathy remain poorly understood, hindering new drug development. Here, we highlight selected key concepts of how the complement system, a major component of innate immunity that is dysregulated in COVID-19, participates in the thromboinflammatory response and drives the vascular endotheliopathy.
Recent Findings:
Recent studies have revealed mechanisms by which complement is activated directly by SARS-CoV-2, and how the system interfaces with other innate thromboinflammatory cellular and proteolytic pathways involving platelets, neutrophils, neutrophil extracellular traps and the coagulation and kallikrein-kinin systems. With this new information, multiple potential sites for therapeutic intervention are being uncovered and evaluated in the clinic.
Summary:
Infections with SARS-CoV-2 cause damage to the lung alveoli and microvascular endothelium via a process referred to as thromboinflammation. Although not alone in being dysregulated, complement is an early player, prominent in promoting the endotheliopathy and consequential organ damage, either directly and/or via the system's complex interplay with other cellular, molecular and biochemical pathways. Delineating these critical interactions is revealing novel and promising strategies for therapeutic intervention.
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