SARS-CoV-2 nonspike structural proteins hijack mucosa epithelial cell fate.

COVID-19 patients readily present with severe epithelial damage, such as tissue ulceration and erosion, along with disrupted tissue repair, in multiple organs. The mucous membranes of the lung alveoli [1, 2], gastrointestinal tract [3, 4], nasal [5] and oral cavity [6, 7] are the primary targets of the SARS-CoV-2 virus. The infected epithelium triggers a dysregulated immune response that further damages tissues and organs [8-10]. Increasing evidence suggests that the SARS-CoV-2 virus can cause direct damage to epithelial cells and fibroblasts [11-13]. Here, we report that the mucosa epithelia of COVID-19 patients can undergo cellular dedifferentiation before any pathological features are observed. SARS-CoV-2 nonspike structural proteins, particularly the Envelope protein, can rapidly induce epithelial cell dedifferentiation, micronuclei formation, cell cycle arrest at the G1 phase and apoptosis. The protein can also severely affect the progenitor cell stratification program. Mechanistically, we identified a unique molecule, calponin 2 (CNN2), as a downstream effector of nonspike structural proteins. Moreover, CNN2 levels were elevated in the epithelia of COVID-19 patients. Downregulating CNN2 could inhibit epithelial cell apoptosis and promote cell differentiation. CNN2 expression is negatively regulated by GLIS2, a transcription factor associated with the disruption of ciliary dynamics in epithelial cells. Therefore, we propose that SARS-CoV-2 damages mucosal epithelium integrity via a novel "double hijack" mechanism: inducing dedifferentiation and disrupting stratification and suggest a new therapeutic target: CNN2 for COVID-19 treatment.