Differences in syncytia formation by SARS-CoV-2 variants modify host chromatin accessibility and cellular senescence via TP53

Abstract

COVID-19 remains a significant public health threat due to the ability of SARS-CoV-2 variants to evade the immune system and cause breakthrough infections. Although pathogenic coronaviruses such as SARS-CoV-2 and MERS-CoV lead to severe respiratory infections, how these viruses affect the chromatin proteomic composition upon infection remains largely uncharacterized. Here we used our recently developed integrative DNA And Protein Tagging (iDAPT) methodology to identify changes in host chromatin accessibility states and chromatin proteomic composition upon infection with pathogenic coronaviruses. SARS-CoV-2 infection induces TP53 stabilization on chromatin, which contributes to its host cytopathic effect. We mapped this TP53 stabilization to the SARS-CoV-2 spike and its propensity to form syncytia, a consequence of cell-cell fusion. Differences in SARS-CoV-2 spike variant-induced syncytia formation modify chromatin accessibility, cellular senescence, and inflammatory cytokine release via TP53. Our findings suggest that differences in syncytia formation alter senescence-associated inflammation, which varies among SARS-CoV-2 variants.

A Tiny Viral Protein, SARS-CoV-2-ORF7b: Functional Molecular Mechanisms

“…However, in specific metabolic contexts, it can induce cell cycle arrest, apoptosis, and changes in metabolism [139]. In fact, researchers have discovered that SARS-CoV-2 infection leads to stabilizing TP53 on chromatin [140], which contributes to a robust host cytopathic effect. The participation of this protein results in the alteration of chromatin accessibility, cellular senescence, and the release of inflammatory cytokines via TP53 in response to various SARS-CoV-2 spike variant-induced syncytia formations.…”

“…The protein appears to have a role in inflammation associated with cellular senescence [140]. In addition, researchers discovered that TP53 plays a role in IFN-γmediated signaling, apoptosis, and proteasomal degradation of CD4 T cells [141].…”