Single-cell characterization of skin response to a bite by West Nile virus-infected mosquito reveals fibroblast-mediated barrier to transmission

Medkour, H.; Bocci, F.; Schneider, N.; Serrato-Pomar, I.; Rey-Cadilhac, F.; Miot, E. F.; Saron, W.; St. John, A.; Maarifi, G.; Liu, Y.; Misse, D.; Nie, Q.; Smith, D. R.; Nisole, S.; Plikus, M.; Pompon, J.

doi:10.64898/2026.01.08.698384

bioRxiv · 10.64898/2026.01.08.698384

Single-cell characterization of skin response to a bite by West Nile virus-infected mosquito reveals fibroblast-mediated barrier to transmission

Medkour, H.·Bocci, F.·Schneider, N.·Serrato-Pomar, I.·Rey-Cadilhac, F.·Miot, E. F.·Saron, W.·St. John, A.·Maarifi, G.·Liu, Y.·Misse, D.·Nie, Q.·Smith, D. R.·Nisole, S.·Plikus, M.·Pompon, J.

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Abstract

Cutaneous events at the mosquito bite site that determine orthoflavivirus transmission efficiency remain largely uncharacterized. Here, we report single-cell RNA-sequencing of skin from immunocompetent mice bitten by West Nile virus-infected mosquitoes, capturing early response at a critical transmission bottleneck. Fibroblasts were the dominant cells exposed to infectious saliva. While neutrophils and Folr2+ macrophages diminished, monocyte-derived and antigen-presenting macrophages, and lymphocytes became more abundant. Cell-cell communication analysis revealed the central roles of fibroblasts and myeloid cells in induced immune-related signaling. Transcriptional profiling defined cell type-specific responses to infectious bite integrating immune modulation, skin repair and metabolic remodeling. Using in vivo gene silencing, we demonstrated that fibroblast-expressed LRRC15 (leucine rich repeat-containing 15) functions as a cutaneous restriction factor, limiting viral replication in skin, viral dissemination to draining lymph nodes, and disease severity. Collectively, our analyses provide cellular and molecular understanding of bite-initiated arboviral transmission, establishing skin-resident fibroblasts as frontline defender cells. HIGHLIGHTSO_LISingle-cell profiling captures early cutaneous response to West Nile virus-infected mosquito bites with cell type resolution. C_LIO_LISkin-resident fibroblasts are the dominant frontline cells exposed to infectious mosquito saliva. C_LIO_LIInfectious bite reconfigures cutaneous immune cells, and activates multi-directional signaling between immune and structural skin cell types. C_LIO_LIBite-induced fibroblast-expressed LRRC15 restricts viral transmission and attenuates disease severity. C_LI

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Medkour, H., Bocci, F., Schneider, N., Serrato-Pomar, I., Rey-Cadilhac, F., Miot, E. F., Saron, W., St. John, A., Maarifi, G., Liu, Y., Misse, D., Nie, Q., Smith, D. R., Nisole, S., Plikus, M., Pompon, J.. 2026-01-09. Single-cell characterization of skin response to a bite by West Nile virus-infected mosquito reveals fibroblast-mediated barrier to transmission. https://doi.org/10.64898/2026.01.08.698384

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