Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 21(5), P. 319 - 329

Published: April 6, 2021

Language: Английский

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

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: 130(11), P. 6151 - 6157

Published: Aug. 6, 2020

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

Language: Английский

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COVID-19 and the human innate immune system

Cell, Journal Year: 2021, Volume and Issue: 184(7), P. 1671 - 1692

Published: Feb. 17, 2021

Language: Английский

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COVID-19: A review of therapeutic strategies and vaccine candidates

Clinical Immunology, Journal Year: 2020, Volume and Issue: 222, P. 108634 - 108634

Published: Nov. 17, 2020

Language: Английский

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Understanding COVID-19-associated coagulopathy

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 22(10), P. 639 - 649

Published: Aug. 5, 2022

Language: Английский

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Patients with COVID-19: in the dark-NETs of neutrophils

Cell Death and Differentiation, Journal Year: 2021, Volume and Issue: 28(11), P. 3125 - 3139

Published: May 24, 2021

SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed curb pandemic, it is paramount define mechanisms develop protective therapies prevent organ dysfunction in patients with COVID-19. Individuals that severe manifestations have signs of dysregulated innate adaptive immune responses. Emerging evidence implicates neutrophils disbalance between neutrophil extracellular trap (NET) formation degradation plays central role pathophysiology inflammation, coagulopathy, damage, immunothrombosis characterize cases Here, we discuss supporting for NETs COVID-19 present putative mechanisms, by which promote tissue injury immunothrombosis. We therapeutic strategies, been successful treatment immunο-inflammatory disorders target NET or degradation, as potential approaches may benefit

Language: Английский

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The state of complement in COVID-19

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 22(2), P. 77 - 84

Published: Dec. 15, 2021

Language: Английский

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Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

Science Immunology, Journal Year: 2021, Volume and Issue: 6(59)

Published: May 13, 2021

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement is a broad indicator critical illness (and thus, no different COVID-19). It also unclear which pathways are contributing COVID-19, and if associated with certain features infection, such as endothelial injury hypercoagulability. To address these questions, we investigated plasma from patients COVID-19 prospectively enrolled at two tertiary care centers: Washington University School Medicine (n=134) Yale (n=49). We compared our non-COVID cohorts: (a) hospitalized influenza (n=54), (b) admitted intensive unit (ICU) acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). demonstrate that circulating markers elevated those non-COVID-19 failure. Further, results facilitate distinguishing who higher risk worse outcomes ICU admission, or IMV. Moreover, indicate enhanced alternative pathway most prevalent (i.e., angiopoietin-2) well hypercoagulability thrombomodulin von Willebrand factor). Our findings identify distinctive feature provide specific targets may utilized for prognostication, drug discovery personalized clinical trials.

Language: Английский

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Complement activation induces excessive T cell cytotoxicity in severe COVID-19

Cell, Journal Year: 2021, Volume and Issue: 185(3), P. 493 - 512.e25

Published: Dec. 28, 2021

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, it remains unclear whether T cells contribute disease pathology. Here, we combined single-cell transcriptomics proteomics with mechanistic studies assess pathogenic cell functions inducing signals. We identified highly activated CD16

Language: Английский

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SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation

Science Immunology, Journal Year: 2021, Volume and Issue: 6(58)

Published: April 2, 2021

Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys and gut. Angiotensin converting enzyme (ACE) 2, best-characterized entry receptor for disease-causing virus SARS-CoV-2, is highly expressed in aforementioned tissues. However, pathways that underlie are still poorly understood. Here, we unexpectedly found complement system was one intracellular most induced by SARS-CoV-2 infection lung epithelial cells. Infection respiratory cells generated activated component C3a could be blocked cell-permeable inhibitor factor B (CFBi), indicating presence an inducible cell-intrinsic C3 convertase Within bronchoalveolar lavage patients, distinct signatures activation myeloid, lymphoid tracked severity. Genes drugs normalize these genes both implicated interferon-JAK1/2-STAT1 signaling NF-κB as main drivers their expression. Ruxolitinib, JAK1/2 inhibitor, normalized interferon signature all gene transcripts cell lines, but did not affect NF-κB-regulated genes. alone or combination antiviral remdesivir, inhibited protein produced infected Together, postulate therapy JAK inhibitors NF-κB-signaling potentially have application severe COVID-19.

Language: Английский

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