@article{9019d2446a2f40fd8461c33ec130e93f,
title = "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",
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 wild type strain or the Alpha and Delta 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.",
keywords = "pericyte, Microvascular disease, COVID-19, Spike protein, CD147, angiotensin converting enzyme 2",
author = "Elisa Avolio and Michele Carrabba and Rachel Milligan and {Kavanagh Williamson}, Maia and Beltrami, {Antonio Paolo} and Kapil Gupta and Elvers, {Karen T} and Monica Gamez and Foster, {R R} and Gillespie, {Kathleen M} and Hamilton, {Fergus W} and Arnold, {David T} and Imre Berger and Davidson, {Andrew D} and Hill, {Darryl J} and Massimo Caputo and Madeddu, {Paolo R}",
note = "Publisher Copyright: {\textcopyright} 2021 The Author(s).",
year = "2021",
month = nov,
day = "22",
doi = "10.1042/CS20210735",
language = "English",
volume = "135",
pages = "2667--2689",
journal = "Clinical Science",
issn = "0143-5221",
publisher = "Portland Press",
number = "24",
}