CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells and its pulmonary levels correlate with viral clearance in critical COVID-19 patients

Barbosa Bomfim, C. C.; Genin, H.; Cottoignies-Callamarte, A.; Gallois-Montbrun, S.; Murigneux, E.; Sams, A.; Rozenberg, A. R.; Belouzard, S.; Dubuisson, J.; Kosminder, O.; Pene, F.; Terrier, B.; Bomsel, M.; Ganor, Y.

doi:10.1101/2024.01.05.574360

bioRxiv · 10.1101/2024.01.05.574360

CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells and its pulmonary levels correlate with viral clearance in critical COVID-19 patients

Barbosa Bomfim, C. C.·Genin, H.·Cottoignies-Callamarte, A.·Gallois-Montbrun, S.·Murigneux, E.·Sams, A.·Rozenberg, A. R.·Belouzard, S.·Dubuisson, J.·Kosminder, O.·Pene, F.·Terrier, B.·Bomsel, M.·Ganor, Y.

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Abstract

Upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with critical coronavirus disease 2019 (COVID-19) present with life-threatening respiratory distress, pulmonary damage and cytokine storm. One unexplored hub in COVID-19 is the neuropeptide calcitonin gene-related peptide (CGRP), which is highly abundant in the airways and could converge in multiple aspects of COVID-19-related pulmonary pathophysiology. Whether CGRP affects SARS-CoV-2 infection directly remains elusive. We show that in critical COVID-19 patients, CGRP is increased in both plasma and lungs. Importantly, CGRP pulmonary levels are elevated in early SARS-CoV-2-positive patients, and restore to baseline upon subsequent viral clearance in SARS-CoV-2-negative patients. We further show that CGRP and its stable analogue SAX directly inhibit infection of bronchial Calu-3 epithelial cells with SARS-CoV-2 Omicron and Alpha variants in a dose-dependent manner. Both pre- and post-infection treatment with GRRP and/or SAX is enough to block SARS-CoV-2 productive infection of Calu3 cells. CGRP-mediated inhibition occurs via activation of the CGRP receptor and involves down-regulation of SARS-CoV-2 entry receptors at the surface of Calu-3 cells. Together, we propose that increased pulmonary CGRP mediates beneficial viral clearance in critical COVID-19 patients, by directly inhibiting SARS-CoV-2 infection. Hence, CGRP-based interventions could be harnessed for management of COVID-19. Brief summaryPulmonary levels of the neuropeptide CGRP are increased in critical COVID-19 patients, and could clear virus by directly inhibiting SRAS-CoV-2 infection of bronchial epithelia cells.

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Barbosa Bomfim, C. C., Genin, H., Cottoignies-Callamarte, A., Gallois-Montbrun, S., Murigneux, E., Sams, A., Rozenberg, A. R., Belouzard, S., Dubuisson, J., Kosminder, O., Pene, F., Terrier, B., Bomsel, M., Ganor, Y.. 2024-01-06. CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells and its pulmonary levels correlate with viral clearance in critical COVID-19 patients. https://doi.org/10.1101/2024.01.05.574360

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