SARS-CoV-2 N protein interacts with Nav1.7 to promote pathological pain

Abstract Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global health crisis, with many patients experiencing not only acute neurological and sensory symptoms but also persistent sensory abnormalities, commonly referred to as long COVID sequelae. The mechanisms underlying somatosensory abnormalities induced by SARS-CoV-2 remain largely unclear. In this study, we investigate the role of the SARS-CoV-2 nucleocapsid (N) protein in pain regulation. Our data show that SARS-CoV-2 N protein exacerbates pathological pain in mouse models of bone cancer, chemotherapy, neuropathic, and inflammatory, and promotes the chronification of acute inflammatory pain. We also identify a potential interaction between the N protein and Na v 1.7 in dorsal root ganglion neurons from mice, monkeys, and humans. Furthermore, the N protein significantly increases Na v 1.7 currents in dorsal root ganglion neurons from both mice and monkeys by delaying Na v 1.7 inactivation without altering its expression or membrane trafficking. This modulation of Na v 1.7 function by the N protein not only intensifies pain hypersensitivity but also prolongs the duration of pain, potentially facilitating the transition from acute to chronic pain. Our findings underscore the importance of vigilant management of SARS-CoV-2 infection in patients with pathological pain and suggest potential therapeutic targets for mitigating COVID-19–related pain.