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

• Published in: bioRxiv 2021-07
• Main Authors: Avolio, Elisa, Carrabba, Michele, Milligan, Rachel, Maia Kavanagh Williamson, Beltrami, Antonio P, Gupta, Kapil, Elvers, Karen T, Gamez, Monica, Foster, Rebecca, Gillespie, Kathleen, Hamilton, Fergus, Arnold, David, Berger, Imre, Caputo, Massimo, Davidson, Andrew D, Hill, Darryl, Madeddu, Paolo
• Format: Article
• Language: English
• Subjects: ACE2; Angiogenesis; Angiotensin; Angiotensin-converting enzyme 2; Apoptosis; Blocking antibodies; CD147 antigen; Cell Biology; Cell proliferation; Cell viability; Coronaviridae; Coronaviruses; COVID-19; Cytokine storm; Cytokines; Endothelial cells; Epithelial cells; Extracellular signal-regulated kinase; Heart; Inflammation; Microvasculature; Peptidyl-dipeptidase A; Pericytes; Phosphorylation; Proteins; Severe acute respiratory syndrome coronavirus 2; Spike protein
• ISSN: 2692-8205
• DOI: 10.1101/2020.12.21.423721

Severe coronavirus disease 2019 (COVID-19) manifests as a life-threatening microvascular syndrome. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the Spike (S) protein to engage with its receptors and infect host cells. To date, it is still not known whether heart vascular pericytes (PCs) are infected by SARS-CoV-2, and if the S protein alone provokes PC dysfunction. Here, we aimed to investigate the effects of the S protein on primary human cardiac PC signalling and function. Results show, for the first time, that cardiac PCs are not permissive to SARS-CoV-2 infection in vitro, whilst a recombinant S protein alone elicits functional alterations in PCs. This was documented as: (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 responsible for 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. In conclusion, our findings suggest that circulating S protein prompts vascular PC dysfunction, potentially contributing to establishing microvascular injury in organs distant from the site of infection. This mechanism may have clinical and therapeutic implications. Competing Interest Statement The authors have declared no competing interest.