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

• Published in: PLoS pathogens 2024-08, Vol.20 (8), p.e1012291
• Main Authors: Li, Huilong, Wan, Luming, Liu, Muyi, Ma, Enhao, Huang, Linfei, Yang, Yilong, Li, Qihong, Fang, Yi, Li, Jingfei, Han, Bingqing, Zhang, Chang, Sun, Lijuan, Hou, Xufeng, Li, Haiyang, Sun, Mingyu, Qian, Sichong, Duan, Xuejing, Zhao, Ruzhou, Yang, Xiaopan, Chen, Yi, Wu, Shipo, Zhang, Xuhui, Zhang, Yanhong, Cheng, Gong, Chen, Gengye, Gao, Qi, Xu, Junjie, Hou, Lihua, Wei, Congwen, Zhong, Hui
• Format: Article
• Language: English
• Subjects: Animals; Biology and Life Sciences; Cell cycle; Cell hybridization; Cellular Senescence; COVID-19 - complications; COVID-19 - metabolism; COVID-19 - pathology; COVID-19 - virology; Development and progression; Extracellular Vesicles - metabolism; Giant Cells - metabolism; Giant Cells - pathology; Giant Cells - virology; Heart failure; Heart Failure - metabolism; Heart Failure - virology; Humans; Medical research; Medicine and Health Sciences; Medicine, Experimental; Mice; Research and analysis methods; Risk factors; SARS-CoV-2; Spike Glycoprotein, Coronavirus - metabolism
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012291

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.