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

Autor:	Barbosa Bomfim CC; Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France.; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France., Génin H; Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France.; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France., Cottoignies-Callamarte A; Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France.; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France., Gallois-Montbrun S; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.; Host-Virus Interactions, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France., Murigneux E; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.; Host-Virus Interactions, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France., Sams A; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Epoqe Pharma, Copenhagen, Denmark., Rosenberg AR; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.; Service of Virology, AP-HP Hôpital Cochin, Paris, France., Belouzard S; Molecular and Cellular Virology of Coronavirus, Infection and Immunity Center of Lille, Institut Pasteur de Lille, Université de Lille, CNRS, INSERM, CHRU, Lille, France., Dubuisson J; Molecular and Cellular Virology of Coronavirus, Infection and Immunity Center of Lille, Institut Pasteur de Lille, Université de Lille, CNRS, INSERM, CHRU, Lille, France., Kosminder O; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.; Service of Biological Hematology, AP-HP Hôpitaux Universitaires Paris Centre, Paris, France., Pène F; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.; Service of Intensive Medicine and Reanimation, AP-HP Hôpital Cochin, Paris, France., Terrier B; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.; Department of Internal Medicine, National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP Hôpital Cochin, Paris, France., Bomsel M; Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France.; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France., Ganor Y; Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, Paris, France.; Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.
Jazyk:	angličtina
Zdroj:	Journal of virology [J Virol] 2024 Sep 17; Vol. 98 (9), pp. e0012824. Date of Electronic Publication: 2024 Aug 20.
DOI:	10.1128/jvi.00128-24
Abstrakt:	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 component 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 restored to baseline upon subsequent viral clearance in SARS-CoV-2-negative patients. We further show that CGRP and its stable analog 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 treatments with CGRP and/or SAX are enough to block SARS-CoV-2 productive infection of Calu-3 cells. CGRP-mediated inhibition occurs via activation of the CGRP receptor and involves down-regulation of both 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 propagation. Hence, CGRP-based interventions could be harnessed for management of COVID-19.IMPORTANCEThe neuropeptide CGRP is highly abundant in the airways. Due to its immunomodulatory, vasodilatory, and anti-viral functions, CGRP could affect multiple aspects of COVID-19-related pulmonary pathophysiology. Yet, the interplay between CGRP and SARS-CoV-2 during COVID-19 remains elusive. Herein, we show that pulmonary levels of CGRP are increased in critical COVID-19 patients, at an early stage of their disease when patients are SARS-CoV-2-positive. Upon subsequent viral clearance, CGRP levels are restored to baseline in SARS-CoV-2-negative patients. We further show that pre- and post-infection treatments with CGRP directly inhibit infection of Calu-3 bronchial epithelial cells with SARS -CoV-2, via activation of the CGRP receptor leading to decreased expression of both SARS-CoV-2 entry receptors. Together, we propose that increased pulmonary CGRP is beneficial in COVID-19, as CGRP-mediated inhibition of SARS-CoV-2 infection could contribute to viral clearance in critical COVID-19 patients. Accordingly, CGRP-based formulations could be useful for COVID-19 management. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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