SARS-CoV-2 directly infects the inner ear and causes hearing dysfunction.

Epidemiological studies have revealed a correlation between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and auditory dysfunction. Here, we demonstrate that intranasal infection of K18-ACE2 mice with four SARS-CoV-2 strains (original, Delta, BA.1, and BA.2) enables the virus to directly invade the inner ear, specifically targeting spiral ganglion neurons (SGNs), leading to increased phase separation and apoptosis in SGNs. Direct infection with different SARS-CoV-2 strains can cause intracellular phase separation and increased neuronal cell apoptosis. Overexpression of the spike protein, mediating viral entry into host cells by binding to cell surface receptors, induces the aberrant aggregation of GTPase-activating protein-binding protein 1 (G3BP1)-positive stress granules by inhibiting the mTOR signaling pathway. This mechanism drives phase separation in neuronal cells and ultimately results in increased apoptosis. Our study unveils an inflammation-independent pathway for SARS-CoV-2-induced hearing loss, centered on direct SGN infection and spike-protein-driven dysregulation of stress granules, thereby providing a critical theoretical foundation for developing targeted therapeutic strategies.