Snail restricts SARS-CoV-2 entry by limiting ACE2 expression as part of broader remodelling of epithelial determinants of viral tropism

Abstract

Pre-existing state of the host cell is a major determinant of the host susceptibility to viral infection. Here, we identify the epithelial-mesenchymal transition transcription factor Snail as a host restriction factor for SARS-CoV-2. Snail loss markedly increased SARS-CoV-2 replication, whereas Snail overexpression and complementation restricted viral replication. Transcriptomic analysis of Snail knockout cells revealed remodelling of epithelial surface-associated programs, including apical membrane, brush border, and junctional pathways. ACE2, the cellular receptor for SARS-CoV-2, was among the genes upregulated in Snail knockout cells. Snail negatively regulated ACE2 transcription, leading to reduced ACE2 transcript and protein abundance and, consequently, lower SARS-CoV-2 entry. Consistent with this, ACE2 promoter activity was higher in Snail knockout cells, which was reduced following Snail complementation. As a means to counter Snail's antiviral functions, SARS-CoV-2 infection progressively depleted Snail protein in different cell culture models, while SNAI1 transcript abundance was surprisingly maintained or increased under the same conditions. Proteasome inhibition and protein-turnover analyses failed to account for this depletion. We find that SARS-CoV-2 infection resulted in reduced association of SNAI1 with polysomes at later stages of infection coinciding with virus-induced host translational suppression, resulting in lower protein synthesis. Together, these findings identify Snail as a regulator of the epithelial entry landscape that limits ACE2-associated SARS-CoV-2 entry and shapes cellular permissiveness, with broader implications for cellular determinants of viral tropism. SARS-CoV-2, in turn, progressively depletes this short-lived antiviral regulator, revealing how virus-induced translational shutoff can remodel pre-existing host cell states and thereby alter cellular susceptibility during infection.