Sahoo, P. P. | Search bioRxiv

bioRxiv2026

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

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.

microbiology↗

bioRxiv2025

MAVS Orchestrates a Potent IFN-independent Antiviral Immunity by Preserving Mitochondrial Integrity

Intrinsic antiviral defenses can restrict infection independent of paracrine interferon (IFN) signaling. While mitochondrial homeostasis is essential for immunity, its direct role in viral restriction remains incompletely understood. Here, we identify mitochondrial antiviral signaling protein (MAVS) as a central effector of a potent IFN-independent antiviral immunity orchestrated though mitochondrial safeguarding. We demonstrate that MAVS is critical for mitochondrial integrity as its loss leads to mitochondrial fragmentation, depolarization, and elevated mitophagy, alongside impaired bioenergetics and protein import. Mechanistically, MAVS maintains mitochondrial integrity by stabilizing the translocase of the outer membrane (TOM) complex and sustaining the abundance of its core components. Remarkably, this mitochondria-driven immunity restricts SARS-CoV-2 replication even under IFN-deficient conditions, and operates alongside the IFN pathways during JEV infection. Our findings redefine MAVS as a mitochondrial guardian that preserves organellar stability to enact host defense. These results highlight mitochondrial integrity as a fundamental determinant of broad antiviral immunity, integrating intrinsic and IFN-dependent mechanisms to counteract viral pathogenesis.

immunology↗