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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.
Avolio, Elisa; Carrabba, Michele; Milligan, Rachel; Kavanagh Williamson, Maia; Beltrami, Antonio P; Gupta, Kapil; Elvers, Karen T; Gamez, Monica; Foster, Rebecca R; Gillespie, Kathleen; Hamilton, Fergus; Arnold, David; Berger, Imre; Davidson, Andrew D; Hill, Darryl; Caputo, Massimo; Madeddu, Paolo.
  • Avolio E; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, U.K.
  • Carrabba M; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, U.K.
  • Milligan R; School of Cellular and Molecular Medicine, University of Bristol, Bristol, U.K.
  • Kavanagh Williamson M; School of Cellular and Molecular Medicine, University of Bristol, Bristol, U.K.
  • Beltrami AP; Department of Pathology, University of Udine, Udine, Italy.
  • Gupta K; School of Biochemistry, University of Bristol, Bristol, U.K.
  • Elvers KT; Medicines Discovery Institute, Cardiff University, Cardiff, U.K.
  • Gamez M; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, U.K.
  • Foster RR; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, U.K.
  • Gillespie K; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, U.K.
  • Hamilton F; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, U.K.
  • Arnold D; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, U.K.
  • Berger I; School of Biochemistry, University of Bristol, Bristol, U.K.
  • Davidson AD; Max Planck Bristol Centre for Minimal Biology, University of Bristol, Bristol, U.K.
  • Hill D; School of Cellular and Molecular Medicine, University of Bristol, Bristol, U.K.
  • Caputo M; School of Cellular and Molecular Medicine, University of Bristol, Bristol, U.K.
  • Madeddu P; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, U.K.
Clin Sci (Lond) ; 135(24): 2667-2689, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1585742
ABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. The capacity of SARS-CoV-2 to infect vascular cells is still debated. Additionally, the SARS-CoV-2 Spike (S) protein may act as a ligand to induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced in the heart of patients with severe coronavirus disease-2019 (COVID-19). Here we newly show that the in vitro exposure of primary human cardiac PCs to the SARS-CoV-2 wildtype strain or the α and δ variants caused rare infection events. Exposure to the recombinant S protein alone elicited signalling and functional alterations, including (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors causing EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation, and rescued PC function in the presence of the S protein. Immunoreactive S protein was detected in the peripheral blood of infected patients. In conclusion, our findings suggest that the S protein may prompt PC dysfunction, potentially contributing to microvascular injury. This mechanism may have clinical and therapeutic implications.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pericytes / Basigin / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / Myocardium Type of study: Prognostic study Topics: Variants Limits: Adolescent / Adult / Aged / Child / Child, preschool / Female / Humans / Infant / Male / Middle aged Language: English Journal: Clin Sci (Lond) Year: 2021 Document Type: Article Affiliation country: Cs20210735

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pericytes / Basigin / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / Myocardium Type of study: Prognostic study Topics: Variants Limits: Adolescent / Adult / Aged / Child / Child, preschool / Female / Humans / Infant / Male / Middle aged Language: English Journal: Clin Sci (Lond) Year: 2021 Document Type: Article Affiliation country: Cs20210735