SARS-CoV-2 spike-induced syncytia are senescent and contribute to exacerbated heart failure

PLoS Pathog. 2024 Aug 5;20(8):e1012291. doi: 10.1371/journal.ppat.1012291. eCollection 2024 Aug.

Abstract

SARS-CoV-2 spike protein (SARS-2-S) induced cell-cell fusion in uninfected cells may occur in long COVID-19 syndrome, as circulating SARS-2-S or extracellular vesicles containing SARS-2-S (S-EVs) were found to be prevalent in post-acute sequelae of COVID-19 (PASC) for up to 12 months after diagnosis. Although isolated recombinant SARS-2-S protein has been shown to increase the SASP in senescent ACE2-expressing cells, the direct linkage of SARS-2-S syncytia with senescence in the absence of virus infection and the degree to which SARS-2-S syncytia affect pathology in the setting of cardiac dysfunction are unknown. Here, we found that the senescent outcome of SARS-2-S induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia without de novo synthesis of SARS-2-S. However, it is important to note that currently approved COVID-19 mRNA vaccines do not induce syncytium formation or cellular senescence. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNFα. We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by SARS-2-S. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy especially in individuals with post-acute sequelae of COVID-19.

MeSH terms

  • Animals
  • COVID-19* / complications
  • COVID-19* / metabolism
  • COVID-19* / pathology
  • COVID-19* / virology
  • Cellular Senescence*
  • Extracellular Vesicles / metabolism
  • Giant Cells* / metabolism
  • Giant Cells* / pathology
  • Giant Cells* / virology
  • Heart Failure* / metabolism
  • Heart Failure* / virology
  • Humans
  • Mice
  • SARS-CoV-2*
  • Spike Glycoprotein, Coronavirus* / metabolism

Substances

  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2

Grants and funding

This work was supported by the Development Program of China grant (2022YFC3600100 to CW) and the National Natural Science Foundation of China grant (32270823 and 32070755 to HZ; 82070595 to CW; 32100558 and 32370178 to LW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.