SARS-CoV-2 proteins regulate inflammatory, thrombotic and diabetic responses in human arterial fibroblasts

Freda, Christopher Thor; Ghebrehiwet, Berhane; Rubenstein, David A.

doi:10.1016/j.clim.2021.108733

Cited by 13 publications

(13 citation statements)

References 54 publications

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“…Finally, adventitial fibroblast gC1qR HK binding site expression was enhanced after exposure to SARS-CoV-2 structural proteins. 11 Therefore, our data is in agreement with previous findings and suggests a link between enhanced inflammation and thrombosis during viral infections. Importantly, COVID-19 patients have been observed to have high incidences of cardiovascular complications, and those patients with underlying vascular complications have higher mortality and morbidity rates as compared with patients without underlying vascular conditions.…”

Section: Discussionsupporting

confidence: 93%

“…This conclusion is in agreement with previous work illustrating that viral exposures (including circovirus, HIV, HCV and adenovirus core proteins) can bind to and inhibit responses from gC1qR. 10 , 25 , 31 , 33 Further, previous work from our lab has illustrated that SARS-CoV-2 structural proteins can interact directly with purified gC1qR (manuscript under review) and with adventitial fibroblast gC1qR 11 (in cell culture) and that under both of these experimental conditions downstream inflammatory and thrombotic responses were enhanced.…”

Section: Discussionsupporting

confidence: 91%

“…We have recently shown that SARS-CoV-2 structural proteins can interact with gC1qR expressed on fibroblasts during altered inflammatory and thrombotic responses. 11 Further, due to the identified role of gC1qR on regulating inflammatory and thrombotic responses observed during vascular pathologies, we chose to investigate how SARS-CoV-2 structural proteins interact with endothelial cell gC1qR. 14 , 15 , 35 , 36 …”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Structural Proteins Exposure Alter Thrombotic and Inflammatory Responses in Human Endothelial Cells

2021

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Introduction We have experienced a pandemic induced by the interaction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) structural proteins with innate structures. These interactions are especially prevalent for patients with underlying pathologies, such as cardiovascular diseases. However, there has been limited work to uncover the range of responses induced by SARS-CoV-2 structural proteins. Thus, our objective was to investigate how endothelial cell pro-thrombotic and pro-inflammatory responses are altered after exposure to SARS-CoV-2 spike, nucleocapsid, and membrane-envelope proteins. We hypothesized that after a short duration exposure, endothelial cells would have a heightened thrombotic and inflammatory potential. With longer exposures, this may lead to altered disease progression and the observed increased mortality and morbidity rates in patients with underlying vascular pathologies. Methods To test this hypothesis, human endothelial cells were exposed to SARS-CoV-2 structural proteins. After the exposure, the expression of thrombomodulin, PECAM-1, connexin-43, and gC1qR were assessed. In parallel, standard cell culture readouts were assessed to determine if these incubations altered cell growth and metabolism. Results and Conclusions We observed significant increases in thrombotic and inflammatory marker expression, with no change to the cell culture parameters (with the exception of a reduction in cell density in response to one SARS-CoV-2 structural protein). Importantly, these observations were dependent on the viral structural protein the cells were exposed to, suggesting that the interactions of SARS-CoV-2 with innate cells is complex and must be uncovered. Combined, this suggests that SARS-CoV-2 structural proteins can regulate inflammatory and thrombotic responses that underlie common pathologies observed during COVID-19.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Structural Proteins Exposure Alter Thrombotic and Inflammatory Responses in Human Endothelial Cells

2021

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“…Fibroblasts were closely associated with alveolar type-2 cells, large thrombi, and interventions such as intubation and treatment [ 8 ]. Moreover, S and N proteins of SARS-CoV-2 are able to induce in vitro the expression of TF on human fibroblasts [ 53 ]. Taken together, it appears that fibroblasts emerge as major players of lung tissue thromboinflammation in progressive COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure

Gavriilidis

Antoniadou

Chrysanthopoulou

et al. 2022

Clinical Immunology

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“…Fibroblasts were closely associated with alveolar type-2 cells, large thrombi, and interventions such as intubation and treatment [8]. Moreover, S and N proteins of SARS-CoV-2 are able to induce in vitro the expression of TF on human fibroblasts [57]. Taken together, it appears that fibroblasts emerge as major players of lung tissue thromboinflammation in progressive COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure

Gavriilidis

Antoniadou

Chrysanthopoulou

et al. 2022

Preprint

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COVID-19-related severe respiratory failure (SRF) leads to mechanical ventilation increasing the in-hospital mortality substantially. Abundancy of lung fibroblasts (LFs) in injured lung tissue has been associated with the progression of respiratory failure in COVID-19. Aiming to reduce mortality in patients with SRF (PaO2/FiO2<100 mmHg) and considering the multi-mechanistic nature of severe COVID-19 pathogenesis, we applied a combined rescue treatment (COMBI) on top of standard-of-care (SOC: dexamethasone and heparin) comprised inhaled DNase to dissolve thrombogenic neutrophil extracellular traps, plus agents against cytokine-mediated hyperinflammation, such as anti-IL-6 receptor tocilizumab and selective JAK1/2 inhibitor baricitinib. COMBI (n=22) was compared with SOC (n= 26), and with two previously and consecutively used therapeutic approaches, including either IL-1 receptor antagonist anakinra (ANA, n=19), or tocilizumab (TOCI, n=11), on top of SOC. In parallel, evaluation of immunothrombosis was assessed in vitro in human LFs, treated with the applied therapeutic agents upon stimulation with COVID-19 plasma. COMBI was associated with lower in-hospital mortality (p=0.014) and intubation rate (p=0.013), shorter duration of hospitalization (p=0.019), and prolonged overall survival after a median follow-up of 110+/-4 days (p=0.003). In vitro, COVID-19 plasma markedly induced tissue factor/thrombin pathway in LFs, while this effect was inhibited by the immunomodulatory agents of COMBI providing a mechanistic explanation for the clinical observations. These results suggest the design of randomized trials using combined immunomodulatory therapies in COVID-19-associated SRF targeting multiple interconnected pathways of immunothrombosis.

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SARS-CoV-2 proteins regulate inflammatory, thrombotic and diabetic responses in human arterial fibroblasts

Cited by 13 publications

References 54 publications

SARS-CoV-2 Structural Proteins Exposure Alter Thrombotic and Inflammatory Responses in Human Endothelial Cells

SARS-CoV-2 Structural Proteins Exposure Alter Thrombotic and Inflammatory Responses in Human Endothelial Cells

Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure

Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure

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