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

• DOI: 10.1101/2022.10.10.511541
• Publication Date: 2022-10-11T22:00:14Z
• Authors: Luming Wan; Huilong Li; Muyi Liu; Enhao Ma; Linfei Huang; Yilong Yang; Qihong Li; Yi Fang; Jingfei Li; Bingqing Han; Chang Zhang; Lijuan Sun; Xufeng Hou; Haiyang Li; Mingyu Sun; Sichong Qian; Xuejing Duan; Ruzhou Zhao; Xiaopan Yang; Yi Chen; Shipo Wu; Xuhui Zhang; Yanhong Zhang; Gong Cheng; Gengye Chen; Qi Gao; Junjie Xu; Lihua Hou; Congwen Wei; Hui Zhong
• Keywords: Syncytium

Abstract Patients with pre-existing heart failure are at a particularly high risk of morbidity and mortality resulting from SARS-CoV-2 infection. Direct acute cardiac injury or cytokine storms have been proposed to contribute depressed function. However, the pathogenic mechanisms underlying increased vulnerability in infected patients still largely unknown. Here, we found that senescent outcome spike protein (SARS-2-S)-induced syncytia exacerbated progression. We first demonstrated syncytium formation cells expressing SARS-2-S delivered by DNA plasmid LNP-mRNA exhibits senescence-like phenotype. Extracellular vesicles containing (S-EVs) also confer potent ability form without denovo synthesis SARS-2-S. Mechanistically, provoke functional MAVS aggregates, which regulate senescence fate TNF α . further demonstrate exhibit shrinked morphology, leading activation WNK1 impaired metabolism. In mice, inhibitor WNK463, anti-syncytial drug niclosamide, senolytic dasatinib protect triggered pseudovirus (SARS-2-Spp). Signs multinucleated identified ascending aorta omicron variant-infected patient. Our findings thus suggest potential mechanism for COVID-19-mediated pathology recommend application therapy. Significance Statement this paper, directly linked SARS-2-S-triggered ensuing induction cellular its pathophysiological contribution failure. propose both expression internalization were sufficient induce nonsenescent ACE2-expressing cells. This is important because persistent existence extracellular during post-acute stages infection human subjects. searching molecular determining syncytial fate, aggregates dependent on RIG-I was observed an early stage fusion regulated anti-death through TNFα-TNFR2 axis. metabolism induced condensed WNK1. Importantly, SARS-2-Spp-exacerbated could be rescued inhibitor, agent. Together, rescuing dysfunction should taken into consideration individuals