Role of the Complement System and Vascular Endothelium in COVID-19 Pathogenesis
Bibliographic record
Abstract
Background: Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 infection has become a global pandemic, presenting with varying degrees of severity from respiratory distress to multi-organ damage. Kidneys are of several organs affected in COVID-19, with acute kidney injury (AKI) being a common consequence, occurring in more than 30% of patients with severe COVID-19. While the underlying mechanisms of COVID-19 pathogenesis remain poorly understood, there is evidence linking complement system overactivation and endothelial injury to organ damage that increases the risk of mortality in COVID-19. Evidence from previous coronavirus epidemics also suggest direct involvement of inflammation, complement dysregulation, and endothelial cell dysfunction. Thus, we hypothesize that vascular endothelial injury resulting from complement overactivation contributes to COVID-19-associated organ injury. Methods: Clinical information and sera from SARS-CoV-2+ patients with mild (n=7) and severe COVID-19 (n=7) diseases were obtained from the Canadian COVID-19 Prospective Cohort Study (CANCOV). Complement activation on ECs was evaluated via immunofluorescence assays, measuring the deposition of complement products C3b and C5b-9 on Human Umbilical Vein Endothelial Cells exposed to control or patient sera. In addition, a permeability assay using a transwell model was used to measure the integrity of the endothelial monolayer exposed to patient sera. Results: Complement was found to be overactivated on ECs treated with SARS-CoV-2+ patient sera compared to those treated with normal human serum as evidenced by significantly increased C3b and C5b-9 deposition. While ECs treated with sera from patients with mild COVID-19 seemed to have higher C3b deposition, ECs treated with sera from patients with severe COVID-19 disease were associated with higher C5b-9 deposition. In addition, increased permeability of the monolayer incubated with SARS-CoV-2+ patient sera was seen over time regardless of disease severity. However, ECs tretaed with severe COVID-19 patient sera had signficiantly increased vascular leakiness as evidenced by increased permeability of the treated monolayer. Conclusions: Thus, we conclude that complement is overactivated in SARS-CoV-2+ patients and use of anti-complement therapies may be an effective strategy in treating COVID-19 associated vascular injury, hyperinflammation, and organ damage.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".