Sphingomyelins in mosquito saliva reconfigure skin lipidome to promote viral protein levels and enhance transmission of flaviviruses

Hacène Medkour; Lauryne Pruvost; Elliott F Miot; Xiaoqian Gong; Virginie Vaissayre; Mihra Tavadia; Pascal Boutinaud; Justine Revel; Atitaya Hitakarun; Wannapa Sornjai; Jim Zoladek; R Duncan Smith; Sébastien Nisole; Esther Nolte-'t Hoen; Justine Bertrand-Michel; Dorothée Missé; Guillaume Marti; Julien Pompon

doi:10.1016/j.cmet.2025.05.015

Sphingomyelins in mosquito saliva reconfigure skin lipidome to promote viral protein levels and enhance transmission of flaviviruses

Hacène Medkour, Lauryne Pruvost, Elliott F Miot, Xiaoqian Gong, Virginie Vaissayre, Mihra Tavadia, Pascal Boutinaud, Justine Revel, Atitaya Hitakarun, Wannapa Sornjai, Jim Zoladek, R Duncan Smith, Sébastien Nisole, Esther Nolte-'t Hoen, Justine Bertrand-Michel, Dorothée Missé, Guillaume Marti, Julien Pompon^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Many flaviviruses with high pandemic potential are transmitted through mosquito bites. While mosquito saliva is essential for transmission and represents a promising pan-flaviviral target, there is a dearth of knowledge on salivary metabolic transmission enhancers. Here, we show that extracellular vesicle (EV)-derived sphingomyelins in mosquito saliva reconfigure the human cell lipidome to increase viral protein levels, boosting skin infection and enhancing transmission for flaviviruses. Lipids within internalized mosquito EVs enhance infection in fibroblast and immune human primary cells for multiple flaviviruses. Mosquito EV lipids selectively increase viral translation by inhibiting infection-induced endoplasmic reticulum (ER)-associated degradation of viral proteins. Infection enhancement solely results from the sphingomyelins within salivary mosquito EVs that augment human cell sphingomyelin concentration. Finally, EV-lipid co-inoculation exacerbates disease severity in vivo in mouse transmission assays. By discovering and elucidating how metabolic components of mosquito saliva promote transmission of flaviviruses, our study unveils lipids as a new category of targets against vectored transmission.

Original language	English
Pages (from-to)	1601-1614.e11
Journal	Cell Metabolism
Volume	37
Issue number	7
Early online date	20 Jun 2025
DOIs	https://doi.org/10.1016/j.cmet.2025.05.015
Publication status	Published - Jul 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors

Funding

We thank Professors Eng Eong Ooi and Mariano Garcia-Blanco for their comments on an earlier version. We extend our gratitude to the members of the Pompon's Laboratory at MIVEGEC, IRD, for their valuable suggestions and support. Special thanks go to Dr. Thierry Durand and Juliette Van-dijk from CNRS, Montpellier, for their assistance. Our appreciation goes to Nathalie Barougier and Drs. Sylvie Cornelie and Idris Mhaidi for their help in mouse management. Additionally, we are grateful to the VectoPole team in Montpellier, particularly Bethsab\u00E9e Scheid and Carole Ginibre, for providing the mosquito eggs. Lipidomic analyses were performed at MetaToul (Toulouse Metabolomics & Fluxomics Facilities, www.mth-metatoul.com), which is part of the French National Infrastructure for Metabolomics and Fluxomics MetaboHUB-ANR-11-INBS-0010. We are grateful to Nancy Geoffre, Amelie Perez, Oc\u00E9ane Delos, and Anaele Durbec for lipid analysis. Support for this research came from fellowships from the Fondation pour la Recherche M\u00E9dicale to H.M. (SPF202110013925) and to E.F.M. (ARF202309017577), Risques Infectieux et Vecteurs en Occitanie (RIVOC) and Key Initiatives MUSE Risques Infectieux et Vecteurs (KIM RIV) grants to H.M. and J.P., French Agence Nationale pour la Recherche (ANR-20-CE15-0006 to J.P. and ANR-21-CE15-0041 to S.N.), and EU HORIZON-HLTH-2023-DISEASE-03-18 (#101137006) and the French National Facility in Metabolomics & Fluxomics, MetaboHUB (11-INBS-0010) to G.M.

Funders	Funder number
Centre National de la Recherche Scientifique
French National Facility in Metabolomics & Fluxomics
Risques Infectieux et Vecteurs en Occitanie
French National Infrastructure for Metabolomics and Fluxomics MetaboHUB-ANR-11-INBS-0010
Institut de recherche pour le développement
French Agence Nationale pour la Recherche	ANR-20-CE15-0006, ANR-21-CE15-0041
Fondation pour la Recherche Médicale	SPF202110013925, ARF202309017577
EU	HORIZON-HLTH-2023-DISEASE-03-18, 101137006
MetaboHUB	11-INBS-0010

Keywords

ERAD
Orthoflavivirus
West Nile
Zika
bite
dengue
extracellular vesicles
lipids
transmission
unfolded protein response

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Sphingomyelins in mosquito saliva reconfigure skin lipidome to promote viral protein levels and enhance transmission of flavivirusesFinal published version, 17.9 MBLicence: CC BY-NC

Cite this

Medkour, H., Pruvost, L., Miot, E. F., Gong, X., Vaissayre, V., Tavadia, M., Boutinaud, P., Revel, J., Hitakarun, A., Sornjai, W., Zoladek, J., Duncan Smith, R., Nisole, S., Nolte-'t Hoen, E., Bertrand-Michel, J., Missé, D., Marti, G., & Pompon, J. (2025). Sphingomyelins in mosquito saliva reconfigure skin lipidome to promote viral protein levels and enhance transmission of flaviviruses. Cell Metabolism, 37(7), 1601-1614.e11. https://doi.org/10.1016/j.cmet.2025.05.015

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abstract = "Many flaviviruses with high pandemic potential are transmitted through mosquito bites. While mosquito saliva is essential for transmission and represents a promising pan-flaviviral target, there is a dearth of knowledge on salivary metabolic transmission enhancers. Here, we show that extracellular vesicle (EV)-derived sphingomyelins in mosquito saliva reconfigure the human cell lipidome to increase viral protein levels, boosting skin infection and enhancing transmission for flaviviruses. Lipids within internalized mosquito EVs enhance infection in fibroblast and immune human primary cells for multiple flaviviruses. Mosquito EV lipids selectively increase viral translation by inhibiting infection-induced endoplasmic reticulum (ER)-associated degradation of viral proteins. Infection enhancement solely results from the sphingomyelins within salivary mosquito EVs that augment human cell sphingomyelin concentration. Finally, EV-lipid co-inoculation exacerbates disease severity in vivo in mouse transmission assays. By discovering and elucidating how metabolic components of mosquito saliva promote transmission of flaviviruses, our study unveils lipids as a new category of targets against vectored transmission.",

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Medkour, H, Pruvost, L, Miot, EF, Gong, X, Vaissayre, V, Tavadia, M, Boutinaud, P, Revel, J, Hitakarun, A, Sornjai, W, Zoladek, J, Duncan Smith, R, Nisole, S, Nolte-'t Hoen, E, Bertrand-Michel, J, Missé, D, Marti, G & Pompon, J 2025, 'Sphingomyelins in mosquito saliva reconfigure skin lipidome to promote viral protein levels and enhance transmission of flaviviruses', Cell Metabolism, vol. 37, no. 7, pp. 1601-1614.e11. https://doi.org/10.1016/j.cmet.2025.05.015

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AU - Medkour, Hacène

AU - Pruvost, Lauryne

AU - Miot, Elliott F

AU - Gong, Xiaoqian

AU - Vaissayre, Virginie

AU - Tavadia, Mihra

AU - Boutinaud, Pascal

AU - Revel, Justine

AU - Hitakarun, Atitaya

AU - Sornjai, Wannapa

AU - Zoladek, Jim

AU - Duncan Smith, R

AU - Nisole, Sébastien

AU - Nolte-'t Hoen, Esther

AU - Bertrand-Michel, Justine

AU - Missé, Dorothée

AU - Marti, Guillaume

AU - Pompon, Julien

PY - 2025/7

Y1 - 2025/7

N2 - Many flaviviruses with high pandemic potential are transmitted through mosquito bites. While mosquito saliva is essential for transmission and represents a promising pan-flaviviral target, there is a dearth of knowledge on salivary metabolic transmission enhancers. Here, we show that extracellular vesicle (EV)-derived sphingomyelins in mosquito saliva reconfigure the human cell lipidome to increase viral protein levels, boosting skin infection and enhancing transmission for flaviviruses. Lipids within internalized mosquito EVs enhance infection in fibroblast and immune human primary cells for multiple flaviviruses. Mosquito EV lipids selectively increase viral translation by inhibiting infection-induced endoplasmic reticulum (ER)-associated degradation of viral proteins. Infection enhancement solely results from the sphingomyelins within salivary mosquito EVs that augment human cell sphingomyelin concentration. Finally, EV-lipid co-inoculation exacerbates disease severity in vivo in mouse transmission assays. By discovering and elucidating how metabolic components of mosquito saliva promote transmission of flaviviruses, our study unveils lipids as a new category of targets against vectored transmission.

AB - Many flaviviruses with high pandemic potential are transmitted through mosquito bites. While mosquito saliva is essential for transmission and represents a promising pan-flaviviral target, there is a dearth of knowledge on salivary metabolic transmission enhancers. Here, we show that extracellular vesicle (EV)-derived sphingomyelins in mosquito saliva reconfigure the human cell lipidome to increase viral protein levels, boosting skin infection and enhancing transmission for flaviviruses. Lipids within internalized mosquito EVs enhance infection in fibroblast and immune human primary cells for multiple flaviviruses. Mosquito EV lipids selectively increase viral translation by inhibiting infection-induced endoplasmic reticulum (ER)-associated degradation of viral proteins. Infection enhancement solely results from the sphingomyelins within salivary mosquito EVs that augment human cell sphingomyelin concentration. Finally, EV-lipid co-inoculation exacerbates disease severity in vivo in mouse transmission assays. By discovering and elucidating how metabolic components of mosquito saliva promote transmission of flaviviruses, our study unveils lipids as a new category of targets against vectored transmission.

KW - ERAD

KW - Orthoflavivirus

KW - West Nile

KW - Zika

KW - bite

KW - dengue

KW - extracellular vesicles

KW - lipids

KW - transmission

KW - unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=105008575300&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2025.05.015

DO - 10.1016/j.cmet.2025.05.015

M3 - Article

C2 - 40543501

SN - 1550-4131

VL - 37

SP - 1601-1614.e11

JO - Cell Metabolism

JF - Cell Metabolism

IS - 7

ER -

Sphingomyelins in mosquito saliva reconfigure skin lipidome to promote viral protein levels and enhance transmission of flaviviruses

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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