CGRP inhibits human Langerhans cells infection with HSV by differentially modulating specific HSV-1 and HSV-2 entry mechanisms

International audienceHerpes simplex virus (HSV) is widespread globally, with both HSV-1 and HSV-2 responsible for genital herpes. During sexual transmission, HSV targets epithelial cells, sensory peripheral pain neurons secreting the mucosal neuropeptide calcitonin generelated peptide (CGRP), and mucosal immune cells including Langerhans cells (LCs). We previously described a neuro-immune crosstalk, whereby CGRP inhibits LCs-mediated human immunodeficiency virus type 1 (HIV-1) transmission. Herein, to further explore CGRP-mediated anti-viral function, we investigated whether CGRP affects LCs infection with HSV. We found that both HSV-1 and HSV-2 primary isolates productively infect monocyte-derived LCs (MDLCs) and inner foreskin LCs. Moreover, CGRP significantly inhibits infection with both HSV subtypes of MDLCs and langerin high , but not langerin low , inner foreskin LCs. For HSV-1, infection is mediated via the HSV-1-specific entry receptor 3-O sulfated heparan sulfate (3-OS HS) in a pH-depended manner, and CGRP downregulates 3-OS HS surface expression, as well as abrogates pH dependency. For HSV-2, infection involves langerin-mediated endocytosis in a pH-independent manner, and CGRP up-regulates surface expression of atypical langerin double-trimer oligomers. Our results show that CGRP inhibits mucosal HSV infection by differentially modulating subtype-specific entry receptors and mechanisms in human LCs. CGRP could turn out useful for prevention of LCs-mediated HSV infection and HSV/HIV-1 co-infection