Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis.

Abstract

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.

• Authors: Panagiotis Skendros, Alexandros Mitsios, Akrivi Chrysanthopoulou, Dimitrios C Mastellos, Simeon Metallidis, Petros Rafailidis, Maria Ntinopoulou, Eleni Sertaridou, Victoria Tsironidou, Christina Tsigalou, Maria Tektonidou, Theocharis Konstantinidis, Charalampos Papagoras, Ioannis Mitroulis, Georgios Germanidis, John D Lambris, Konstantinos Ritis
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 130 Issue 11 Pg. 6151-6157 (11 02 2020) ISSN: 1558-8238 [Electronic] United States
• PMID: 32759504 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• C5AR1 protein, human
• Complement Membrane Attack Complex
• Peptides, Cyclic
• Receptor, Anaphylatoxin C5a
• compstatin
• Thromboplastin
• Thrombin

Topics

• Aged
• Betacoronavirus (immunology, metabolism)
• COVID-19
• Complement Activation (drug effects)
• Complement Membrane Attack Complex (immunology, metabolism)
• Coronavirus Infections (blood, immunology)
• Extracellular Traps (immunology, metabolism)
• Female
• Humans
• Male
• Middle Aged
• Neutrophils (immunology, metabolism)
• Pandemics
• Peptides, Cyclic (pharmacology)
• Pneumonia, Viral (blood, immunology)
• Receptor, Anaphylatoxin C5a (antagonists & inhibitors, blood, immunology)
• Respiratory Distress Syndrome (blood, immunology, virology)
• SARS-CoV-2
• Thrombin (immunology, metabolism)
• Thromboplastin (immunology, metabolism)
• Thrombosis (blood, immunology, virology)