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

Abstract

Herpes 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 gene-related 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 langerinhigh, but not langerinlow, 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 down-regulates 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.

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Fig. 1: Human LCs express HSV-1 and HSV-2 entry receptors.
Fig. 2: Human MDLCs are productively infected with HSV-1 and HSV-2.
Fig. 3: Human inner foreskin langerin-expressing cells are productively infected with HSV-1 and HSV-2.
Fig. 4: CGRP inhibits human LCs infection with HSV-1 and HSV-2.
Fig. 5: CGRP decreases 3-OS HS expression and abrogates pH dependency during HSV-1 infection of human LCs.
Fig. 6: CGRP inhibits langerin-mediated HSV-2 infection of human LCs and induces atypical langerin double trimers.
Fig. 7: Summary of HSV-1 and HSV-2 infection mechanisms in human LCs, and their inhibition by CGRP.

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Acknowledgements

This study was funded by a research grant (to Y.G.) and PhD fellowships (to E.C. and J.M.) from Agence Nationale de la Recherches sur le Sida et les Hépatites virales (ANRS) | Maladies Infectieuses Émergentes, and by a research grant (to M.B.) from Fondation pour la Recherche Medicale (Équipe FRM).

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E.C., J.M., and Y.G. performed the experiments; F.R. provided primary HSV isolates; A.S. prepared and provided SAX; T.H.vK prepared and provided clone HS4C3 against 3-OS HS; N.B.D. and M.Z. provided foreskin tissues; Y.G. and M.B. designed the experiments; Y.G. conceived the study and wrote the paper.

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Correspondence to Yonatan Ganor.

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Cohen, E., Mariotton, J., Rozenberg, F. et al. CGRP inhibits human Langerhans cells infection with HSV by differentially modulating specific HSV-1 and HSV-2 entry mechanisms. Mucosal Immunol 15, 762–771 (2022). https://doi.org/10.1038/s41385-022-00521-y

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