ArticleBlood2020
Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition.
Article in Blood, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 245 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
245 citing papers in PubMed, 1 synthesis or guideline pooled it, 387 citations in OpenAlex.
- Mucosal immune response in biology, disease prevention and treatment.Signal transduction and targeted therapy · 2025Pooled it
- Recombinant C1 inhibitor in the prevention of severe COVID-19: a randomized, open-label, multi-center phase IIa trial.Frontiers in immunology · 2023Trial
- Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial.Respiratory research · 2022Trial
- Complement system component dysregulation is a distinctive feature of COVID-19 disease: a prospective and comparative analysis of patients admitted to the emergency department for suspected COVID-19 disease.Journal of thrombosis and thrombolysis · 2022Trial
- Transcriptome, Proteome, and Metabolome Features in Diarrhea Challenge of Preweaning Piglets via Multi-Omics Integration Analyses.Animals : an open access journal from MDPI · 2026Article
- Collectin-11, a complement pattern recognition molecule, mediates pulmonary SARS-CoV-2 neutralization and protection.PLoS pathogens · 2026Article
- C3 p.Asp1115Asn Variant-associated Atypical Hemolytic Uremic Syndrome with Spontaneous Remission Triggered by Influenza and COVID-19.Internal medicine (Tokyo, Japan) · 2026Article
- Review
- Pathogenesis of Non-Arteritic Anterior Ischemic Optic Neuropathy Associated with COVID-19.International journal of molecular sciences · 2026Review
- SARS-CoV-2 spike S1-mediated HIF-2α activation in retinal endothelial cells suggests a mechanism contributing to post-COVID endothelial dysfunction.Frontiers in immunology · 2026Article
- Emergency use of eculizumab in impending and manifest myasthenic crisis: a retrospective case series.Therapeutic advances in neurological disorders · 2026Article
- Review
- Impact of complement system proteins on the clinical progression of hospitalized patients with COVID-19.BMC infectious diseases · 2025Article
- Engineered Dual-Function Antibody-Like Proteins to Combat SARS-CoV-2-Induced Immune Dysregulation and Inflammation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The role of complement in long COVID pathogenesis.JCI insight · 2025Review
- Do Long COVID and COVID Vaccine Side Effects Share Pathophysiological Picture and Biochemical Pathways?International journal of molecular sciences · 2025Review
- Multisystem Endothelial Inflammation: A Key Driver of Adverse Events Following mRNA-Containing COVID-19 Vaccines.Vaccines · 2025Review
- Complement Activation is More Pronounced in the Kidneys of Critically Ill Patients With COVID-19 Than in Those With Bacterial Sepsis.Kidney international reports · 2025Article
- Is COVID-19 Coagulopathy a Thrombotic Microangiopathy? A Prospective, Observational Study.International journal of molecular sciences · 2025Observational
- The involvement of mitochondria in erythrocyte pathology and diseases: from mechanisms to therapeutic strategies.Clinical and experimental medicine · 2025Review
185 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein-treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.