SARS-CoV-2 spike-induced syncytia are senescent and contribute to exacerbated heart failure
SARS-CoV-2 spike protein (SARS-2-S) may drive cell-cell fusion in uninfected cells, which could contribute to long COVID-19 symptoms. Circulating SARS-2-S or extracellular vesicles containing the spike protein (S-EVs) have been detected in individuals with post-acute sequelae of COVID-19 (PASC) for up to 12 months after diagnosis. While recombinant SARS-2-S protein has been shown to enhance the senescence-associated secretory phenotype (SASP) in ACE2-expressing cells, the direct connection between SARS-2-S-induced syncytia and cellular senescence, as well as its role in cardiac dysfunction, is not well understood.
In this study, we discovered that SARS-2-S-induced syncytia contribute to the worsening of heart failure. We demonstrated that cells expressing SARS-2-S, delivered via DNA plasmid or LNP-mRNA, exhibit a senescence-like phenotype. Additionally, extracellular vesicles containing SARS-2-S (S-EVs) can promote the formation of senescent syncytia without the need for new SARS-2-S synthesis. However, it is important to emphasize that currently approved COVID-19 mRNA vaccines do not cause syncytium formation or cellular senescence.
On a mechanistic level, SARS-2-S syncytia trigger the formation of MAVS aggregates, which determine the senescent fate of these syncytia via TNFα. Moreover, senescent SARS-2-S syncytia display a shrunken morphology, leading to the activation of WNK1 and disruption of cardiac metabolism. In a mouse model of pre-existing heart failure, treatment with the WNK1 inhibitor WNK463, the anti-syncytial drug niclosamide, or the senolytic drug dasatinib protected the heart from the worsening of heart failure caused by SARS-2-S.
These findings propose a potential mechanism for COVID-19-related heart issues and suggest that WNK1 inhibitors may be a promising therapeutic approach, particularly for individuals with post-acute COVID-19 complications.