SARS-CoV-2 Spike Proteins and Cell–Cell Communication Inhibits TFPI and Induces Thrombogenic Factors in Human Lung Microvascular Endothelial Cells and Neutrophils: Implications for COVID-19 Coagulopathy Pathogenesis DOI Open Access

Biju Bhargavan,

Georgette D. Kanmogne

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(18), P. 10436 - 10436

Published: Sept. 9, 2022

In SARS-CoV-2-infected humans, disease progression is often associated with acute respiratory distress syndrome involving severe lung injury, coagulopathy, and thrombosis of the alveolar capillaries. The pathogenesis these pulmonary complications in COVID-19 patients has not been elucidated. Autopsy study showed SARS-CoV-2 virions vessels sequestrated leukocytes infiltrates endotheliopathy microvascular thrombosis. Since enters infects target cells by binding its spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2), there evidence that vascular endothelial neutrophils express ACE2, we investigated effect S-proteins cell-cell communication on primary human (HLMEC) expression thrombogenic factors potential mechanisms. Using two different variants (Wuhan Delta), demonstrate exposure HLMEC or S-proteins, co-culture exposed non-exposed neutrophils, induced transcriptional upregulation tissue factor (TF), significantly increased secretion (F)-V, thrombin, fibrinogen inhibited pathway inhibitor (TFPI), regulator extrinsic blood coagulation, both cell types. Recombinant (r)TFPI a thiol blocker (5,5'-dithio-bis-(2-nitrobenzoic acid)) prevented S-protein-induced Factor-V, fibrinogen. Thrombomodulin blocked but had no Factor-V thrombin. These results suggests following contact endothelium endothelial-neutrophil interactions, viral induce coagulopathy via TF mechanisms functional groups. findings suggest using rTFPI and/or thiol-based drugs could be viable therapeutic strategy against SARS-CoV-2-induced

Language: Английский

SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19 DOI Creative Commons

Lize M. Grobbelaar,

Chantelle Venter,

Maré Vlok

et al.

Bioscience Reports, Journal Year: 2021, Volume and Issue: 41(8)

Published: July 30, 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One most important pathologies, hypercoagulation and microclots in lungs patients. Here we study effect isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron fluorescence microscopy well mass spectrometry, investigate this to interact with platelets fibrin(ogen) directly blood hypercoagulation. platelet-poor plasma (PPP), show that may interfere flow. Mass spectrometry also showed when added healthy PPP, it results structural changes β γ fibrin(ogen), complement 3, prothrombin. These proteins were substantially resistant trypsinization, presence S1. suggest that, part, circulation contribute COVID-19 positive patients substantial impairment fibrinolysis. Such lytic result persistent large have noted here previously samples This observation relevance treatment hypercoagulability

Language: Английский

Citations

160
The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease DOI Creative Commons
Elisa Avolio, Michele Carrabba, Rachel Milligan

et al.

Clinical Science, Journal Year: 2021, Volume and Issue: 135(24), P. 2667 - 2689

Published: Nov. 22, 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. capacity SARS-CoV-2 to infect vascular cells is still debated. Additionally, the Spike (S) protein may act as ligand induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced heart patients with disease-2019 (COVID-19). Here we newly show that vitro exposure primary human cardiac PCs wildtype strain or α and δ variants caused rare infection events. Exposure recombinant S alone elicited signalling functional alterations, including: (1) increased migration, (2) ability support endothelial cell (EC) network formation on Matrigel, (3) secretion pro-inflammatory molecules typically involved cytokine storm, (4) production pro-apoptotic factors causing EC death. Next, adopting blocking strategy against receptors angiotensin-converting enzyme (ACE2) CD147, discovered stimulates phosphorylation/activation extracellular signal-regulated kinase 1/2 (ERK1/2) through CD147 receptor, but not ACE2, PCs. neutralisation either using antibody mRNA silencing, ERK1/2 activation, rescued PC function presence protein. Immunoreactive was detected peripheral blood infected patients. In conclusion, our findings suggest prompt dysfunction, potentially contributing injury. This mechanism have therapeutic implications.

Language: Английский

Citations

82
Evidence For and Against Direct Kidney Infection by SARS-CoV-2 in Patients with COVID-19 DOI
Luise Hassler,

Fabiola Reyes,

Matthew A. Sparks

et al.

Clinical Journal of the American Society of Nephrology, Journal Year: 2021, Volume and Issue: 16(11), P. 1755 - 1765

Published: June 14, 2021

Despite evidence of multiorgan tropism severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with disease 2019 (COVID-19), direct viral kidney invasion has been difficult to demonstrate. The question whether SARS-CoV2 can directly infect the is relevant understanding pathogenesis AKI and collapsing glomerulopathy COVID-19. Methodologies document SARS-CoV-2 infection that have used include immunohistochemistry, immunofluorescence, RT-PCR, situ hybridization, electron microscopy. In our review studies date, we found kidneys COVID-19 was detected 18 94 (19%) by 71 144 (49%) 11 84 (13%) hybridization. a smaller number examined 10 13 (77%). total, from 102 235 (43%), presence suggested at least one methods used. these positive findings, caution needed because many other negative for it should be noted when detected, only obtained autopsy. There clear need biopsies, including those performed early stages COVID-19–associated disease. Development tests detect urine samples would more practical as noninvasive way evaluate during evolution

Language: Английский

Citations

68
SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling DOI Creative Commons
Scott B. Biering, Francielle Tramontini Gomes de Sousa, Laurentia V. Tjang

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Dec. 9, 2022

Abstract Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well in distal organs. While it appreciated that an exaggerated inflammatory response dysfunction, triggers of vascular leak are unclear. Here, we report cell-intrinsic interactions between Spike (S) glycoprotein SARS-CoV-2 epithelial/endothelial cells sufficient to induce vitro vivo, independently viral replication ACE2 receptor. We identify S-triggered transcriptional extracellular matrix reorganization TGF-β signaling. Using genetic knockouts specific inhibitors, demonstrate glycosaminoglycans, integrins, signaling axis required for S-mediated dysfunction. Notably, show infection caused which was reduced by inhibiting integrins. Our findings offer mechanistic insight into SARS-CoV-2-triggered leak, providing a starting point development therapies targeting COVID-19.

Language: Английский

Citations

50
COVID-19 and Glomerular Diseases DOI Creative Commons
Nattawat Klomjit, Ladan Zand, Lynn D. Cornell

et al.

Kidney International Reports, Journal Year: 2023, Volume and Issue: 8(6), P. 1137 - 1150

Published: March 27, 2023

Language: Английский

Citations

28
SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19 DOI Creative Commons
Zhouyi Rong, Hongcheng Mai,

Saketh Kapoor

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 5, 2023

ABSTRACT Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been associated mainly with a range of neurological symptoms, including brain fog and tissue loss, raising concerns about virus’s potential chronic impact on central nervous system. In this study, we utilized mouse models human post-mortem tissues to investigate presence distribution SARS-CoV-2 spike protein in skull-meninges-brain axis. Our results revealed accumulation skull marrow, meninges, parenchyma. The injection alone cell death brain, highlighting direct effect tissue. Furthermore, observed deceased long after their COVID-19 infection, suggesting that spike’s persistence may contribute long-term symptoms. was neutrophil-related pathways dysregulation proteins involved PI3K-AKT as well complement coagulation pathway. Overall, our findings suggest trafficking from CNS borders into parenchyma identified differentially regulated present insights mechanisms underlying immediate consequences diagnostic therapeutic opportunities. Graphical Summary Short axis presents molecular targets for complications long-COVID-19 patients .

Language: Английский

Citations

25
SARS-CoV-2 S1 subunit produces a protracted priming of the neuroinflammatory, physiological, and behavioral responses to a remote immune challenge: A role for corticosteroids DOI
Matthew G. Frank, Jayson B. Ball, Shelby Hopkins

et al.

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 121, P. 87 - 103

Published: July 21, 2024

Language: Английский

Citations

6
Long COVID and COVID-19-associated cystitis (CAC) DOI Creative Commons
Laura E. Lamb,

Ryan Timar,

Mélissa Wills

et al.

International Urology and Nephrology, Journal Year: 2021, Volume and Issue: 54(1), P. 17 - 21

Published: Nov. 17, 2021

Language: Английский

Citations

33
A Functional Interaction Between Y674-R685 Region of the SARS-CoV-2 Spike Protein and the Human α7 Nicotinic Receptor DOI Open Access
Juan Facundo Chrestia, A. Sofia F. Oliveira, Adrian J. Mulholland

et al.

Molecular Neurobiology, Journal Year: 2022, Volume and Issue: 59(10), P. 6076 - 6090

Published: July 20, 2022

Language: Английский

Citations

23
SARS-CoV-2 Spike Proteins and Cell–Cell Communication Induce P-Selectin and Markers of Endothelial Injury, NETosis, and Inflammation in Human Lung Microvascular Endothelial Cells and Neutrophils: Implications for the Pathogenesis of COVID-19 Coagulopathy DOI Open Access

Biju Bhargavan,

Georgette D. Kanmogne

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12585 - 12585

Published: Aug. 9, 2023

COVID-19 progression often involves severe lung injury, inflammation, coagulopathy, and leukocyte infiltration into pulmonary tissues. The pathogenesis of these complications is unknown. Because vascular endothelium neutrophils express angiotensin-converting enzyme-2 spike (S)-proteins, which are present in bodily fluids tissues SARS-CoV-2-infected patients, we investigated the effect S-proteins cell-cell communication on human microvascular endothelial cells expression P-selectin, markers NETosis, inflammation. Exposure or to endothelial-neutrophils co-culture induced P-selectin transcription expression, significantly increased expression/secretion IL-6, von Willebrand factor (vWF, pro-coagulant), citrullinated histone H3 (cit-H3, NETosis marker). Compared SARS-CoV-2 Wuhan variant, Delta variant 1.4-15-fold higher IL-6 vWF. Recombinant tissue pathway inhibitor (rTFPI), 5,5'-dithio-bis-(2-nitrobenzoic acid) (thiol blocker), thrombomodulin (anticoagulant) blocked S-protein-induced vWF, cit-H3. This suggests that following contact with endothelial-neutrophil interactions, increase adhesion molecules, induce coagulopathy via pathway, mechanisms involving functional thiol groups, and/or fibrinolysis system. Using rTFPI, effectors system thiol-based drugs could be viable therapeutic strategies against SARS-CoV-2-induced coagulopathy.

Language: Английский

Citations

15