PDF(Pubmed)
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.
摘要：
SARS-CoV-2刺突蛋白（SARS-2-S）诱导的未感染细胞中的细胞-细胞融合可能发生在长的COVID-19综合征中，因为发现循环的SARS-2-S或含有SARS-2-S的细胞外囊泡（S-EV）在诊断后的12个月内流行于COVID-19（PASC）的急性后遗症中。尽管已显示分离的重组SARS-2-S蛋白在衰老的ACE2表达细胞中增加SASP，在没有病毒感染的情况下，SARS-2-S合胞体与衰老的直接联系以及SARS-2-S合胞体对心功能不全的病理影响程度尚不清楚。这里,我们发现SARS-2-S诱导的合胞体的衰老结局加剧了心力衰竭的进展。我们首先证明了通过DNA质粒或LNP-mRNA传递的表达SARS-2-S的细胞中合胞体的形成表现出衰老样表型。含有SARS-2-S（S-EV）的胞外囊泡还赋予了形成衰老合胞体的有效能力，而无需SARS-2-S的从头合成。然而,值得注意的是，目前批准的COVID-19mRNA疫苗不会诱导合胞体形成或细胞衰老。机械上,SARS-2-S合胞体引起功能性MAVS聚集体的形成，通过TNFα调节SARS-2-S合胞体的衰老命运。我们进一步证明，衰老的SARS-2-S合胞体表现出收缩的形态，导致WNK1激活和心脏代谢受损。在先前存在的心力衰竭小鼠中，WNK1抑制剂WNK463，抗合胞药氯硝柳胺，和溶血性达沙替尼保护心脏免受SARS-2-S引发的加剧的心力衰竭。因此，我们的发现提示了COVID-19介导的心脏病理的潜在机制，并建议将WNK1抑制剂用于治疗，特别是在患有COVID-19急性后后遗症的个体中。
