Background
One important defense mechanism against invading pathogens involves interactions between sensory peripheral nociceptor pain neurons innervating all mucosal tissues, and resident immune and epithelial cells. We discovered that the nociceptor-secreted neuropeptide calcitonin gene-related peptide (CGRP) exerts unexpected anti-viral functions. CGRP acts on antigen-presenting Langerhans cells (LCs) and inhibits their infections with human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2), which synergize during their co-infection.
Recent results
HIV-1: CGRP secretion is induced upon activation of the Ca2+ ion channel transient receptor potential vanilloid 1 (TRPV1) in nociceptors. We found that this mechanism operates also in LCs, for instance the natural TRPV1 agonist cannabidiol (CBD) from Marijuana activates TRPV1 in LCs, inducing their secretion of CGRP that inhibits LCs-mediated HIV-1 transfer to CD4+ T-cells. CBD also inhibits direct HIV-1 infection of CD4+ T-cells in CGRP-independent manners. These studies support re-positioning of CBD-based formulations as novel HIV-1 pre-exposure prophylaxis (PrEP) measures, i.e. CBD PrEP.
HSV-2: To better mimic the neuroimmune tissue architecture, we developed a microfluidic ‘mucosa-on-chip’ model, combining CGRP+ nociceptors with genital epithelial cells and LCs. In this model, LCs relay HSV-2 to nociceptor axonal endings, leading to axonal degeneration and CGRP reduction. These studies suggest active roles of LCs in HSV-2 infection and latency establishment in nociceptors.
SARS-CoV-2: CGRP could control coronavirus disease 19 (COVID-19) symptoms, due to its anti-hypertensive/inflammatory functions. We found elevated CGRP pulmonary levels in early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive, but not late SARS-CoV-2-negative, critical COVID-19 patients. Moreover, CGRP acts directly on bronchial epithelial cells, decreasing their surface expression of SARS-CoV-2 entry receptors thereby inhibiting their infection. These studies indicate that CGRP mediates beneficial SARS-CoV-2 clearance.
Significance
Our studies identify novel mucosal neuroimmune and neuroepithelial interactions, which could be harnessed clinically against a variety of mucosal viruses.