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

Elisa Avolio*, Michele Carrabba, Rachel Milligan, Maia Kavanagh Williamson, Antonio Paolo Beltrami, Kapil Gupta, Karen T Elvers, Monica Gamez, R R Foster, Kathleen M Gillespie, Fergus W Hamilton, David T Arnold, Imre Berger, Andrew D Davidson, Darryl J Hill, Massimo Caputo, Paolo R Madeddu

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

82 Citations (Scopus)
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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.
Original languageEnglish
Article numberCS20210735
Pages (from-to)2667-2689
Number of pages23
JournalClinical Science
Volume135
Issue number24
Early online date22 Nov 2021
DOIs
Publication statusPublished - 22 Nov 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s).

Structured keywords

  • Covid19

Keywords

  • pericyte
  • Microvascular disease
  • COVID-19
  • Spike protein
  • CD147
  • angiotensin converting enzyme 2

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