Pellino-1, a therapeutic target for control of SARS-CoV-2 infection and disease severity.

Enhanced expression of Pellino-1 (Peli1), a ubiquitin ligase is known to be associated with COVID-19 susceptibility. The underlying mechanisms are not known. Here, we report that mice deficient in Peli1 (Peli1) had reduced viral load and attenuated inflammatory immune responses and tissue damage in the lung following SARS-CoV-2 infection. Overexpressing Peli1 in 293 T cells increased SARS-CoV-2 infection via promoting virus replication and transcription, without affecting virus attachment and entry into the cells. Smaducin-6 treatment which is known to disrupt Peli1-mediated NF-KB activation, attenuated inflammatory immune responses in human lung epithelial cells as well as in the lung of K18-hACE2 mice following SARS-CoV-2 infection, though it had minimal effects on SARS-CoV-2 infection in human nasal epithelial cells. Overall, our findings suggest that Peli1 contributes to SARS-CoV-2 pathogenesis by promoting virus replication and positively regulating virus-induced inflammatory responses in lung epithelial cells. Peli1 is a therapeutic target to control SARS-CoV-2 -induced disease severity.