Sand fly saliva reprograms skin fibroblasts to enhance arbovirus infection
Arbovirus transmission by sand flies is a growing public health concern, yet the early skin events shaping infection outcomes remain undefined. We establish a mouse model of Toscana virus (TOSV) infection that incorporates sand fly salivary factors to mimic natural transmission. Saliva from two distinct sand fly genera significantly enhanced infection and promoted neurological signs and joint inflammation, recapitulating key features of human TOSV disease. In the skin, dermal macrophages and fibroblasts were the main infected cell types, but only fibroblasts generated infectious virus. Saliva reprogrammed fibroblasts into a wound-healing state permissive to viral replication, driving local viral amplification, systemic spread, and thereby clinical disease. These findings identify skin fibroblasts as central determinants of host susceptibility and reveal that sand fly saliva actively remodels the skin to exacerbate viral pathogenesis. This work redefines the skin's role in sand fly-transmitted infection and highlights new targets for therapeutic and vaccine development.
Authors
- Kave Shams (ORCID: https://orcid.org/0000-0002-8145-5351)
- Alain Kohl (ORCID: https://orcid.org/0000-0002-1523-9458)
- Magdalena Jančářová (ORCID: https://orcid.org/0000-0003-0273-3446)
- Maria Grazia Cusi (ORCID: https://orcid.org/0000-0001-8869-8164)
- Clive S. McKimmie (ORCID: https://orcid.org/0000-0002-7694-9509)
- Petr Volf (ORCID: https://orcid.org/0000-0003-1790-1123)
- Matthew E. Rogers (ORCID: https://orcid.org/0000-0002-6542-6438)
- Akira J. T. Alexander (ORCID: https://orcid.org/0000-0003-1601-619X)
- Liam Barningham (ORCID: https://orcid.org/0009-0008-3851-680X)
- Yonca Keşkek Türk (ORCID: https://orcid.org/0000-0002-7955-086X)
- Ailish McCafferty-Brown
- Çağdaş Kaya
- Scott MacDonald (ORCID: https://orcid.org/0000-0003-0797-656X)
Institutions
- University of Siena (IT)
- University of Leeds (GB)
- Liverpool School of Tropical Medicine (GB)
- Charles University (CZ)
- London School of Hygiene & Tropical Medicine (GB)
- NIHR Leeds Musculoskeletal Biomedical Research Unit (GB)
- MRC University of Glasgow Centre for Virus Research (GB)
- Maltepe University (TR)
- University of York (GB)
- Hull York Medical School (GB)
Publication Details
- Journal
- iScience
- Published
- 2025-10-25
- DOI
- https://doi.org/10.1016/j.isci.2025.113854
- Primary Topic
- Viral Infections and Vectors
- Type
- article
- Field-Weighted Citation Impact
- 0.00