The neuropeptide "calcitonin gene-related peptide" (CGRP) is a potent vasodilator and immunomodulator, secreted by peripheral sensory neurons innervating the respiratory pathways.
In a study published in the
Journal of Virology, scientists reveal a new antiviral function of CGRP. This beneficial activity of CGRP represents a new protective mechanism that could be harnessed for managing COVID-19.
CGRP, a multifaceted neuropeptide
CGRP is a powerful vasodilator, leading to opposing effects in different pathologies, for example inducing migraine but protecting against cardiovascular diseases. This neuropeptide is secreted by peripheral sensory neurons that transmit pain, called nociceptors, which innervate all internal organs and tissues. When secreted at the mucosal level, CGRP is also involved in neuro-immune interactions, independent of its vasodilatory function, but which directly affect the functioning of various immune cells.
Renewed interest in CGRP has revealed its important and previously unknown roles during infection. For example, in previous studies, scientists discovered that CGRP exerts a robust antiviral function. Indeed, by acting on Langerhans cells, which are antigen-presenting cells, CGRP strongly inhibits their infection by sexually transmitted viruses.
CGRP is abundant in the respiratory pathways, where it is secreted both by nociceptors innervating the lungs and by pulmonary neuroendocrine cells (PNECs). Due to its antihypertensive and anti-inflammatory effects, CGRP could control multiple aspects of pulmonary pathophysiology related to COVID-19.
Therapeutic potential in the fight against Covid-19
In an article published in the
Journal of Virology, scientists sought to determine whether CGRP's antiviral function extended to respiratory viruses, focusing on SARS-CoV-2.
CGRP inhibits infection by SARS-CoV-2.
The pseudostratified bronchial epithelium is composed of different types of epithelial cells, such as secretory and ciliated cells (1). It also contains PNECs (2) and is innervated by nociceptors (3), which are the two main cellular sources secreting CGRP in the lungs. During COVID-19, SARS-CoV-2 primarily infects ciliated epithelial cells (4), leading to damage and a cytokine storm. This study reveals that CGRP decreases the expression of SARS-CoV-2 entry receptors in bronchial epithelial cells, thereby inhibiting their productive infection by SARS-CoV-2 (5).
© Yonatan GANOR
In collaboration with several clinicians, scientists demonstrate that in patients with critical COVID-19, CGRP levels are increased in bronchoalveolar lavages (BALs). More specifically, CGRP levels in BALs are elevated when patients test positive for SARS-CoV-2 and return to baseline levels when patients subsequently test negative for SARS-CoV-2.
Scientists also show, through in vitro studies on the Calu-3 bronchial epithelial cell line, that CGRP directly inhibits infection by both Omicron and Alpha variants of SARS-CoV-2, whether the neuropeptide is added before or after infection. Such inhibition involves the activation of the CGRP receptor, leading to a reduction in the surface expression of SARS-CoV-2 entry receptors.
These findings on CGRP's control of SARS-CoV-2 replication suggest that CGRP induces a beneficial and endogenous protective mechanism, similar to what has been observed in other pulmonary pathologies (such as asthma and cystic fibrosis). Consequently, elevated pulmonary CGRP does not cause damage but rather constitutes a compensatory protective response, mediating beneficial viral clearance in patients with critical COVID-19.
Scientists now propose that formulations containing CGRP, or inducing its secretion, could be useful in the prevention and treatment of critical COVID-19, as a complement to COVID-19 vaccines and antiviral drugs against SARS-CoV-2.
References:
CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells and its pulmonary levels correlate with viral clearance in critical COVID-19 patients.
Journal of Virology. 2024.
DOI:
10.1128/jvi.00128-24