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.

Centre for Neglected Tropical Diseases Departments of Tropical Disease Biology and Vector Biology Liverpool School of Tropical Medicine Pembroke Place Liverpool UK

Department of Disease Control Faculty of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine London UK

Department of Parasitology Faculty of Science Charles University 128 00 Prague Czech Republic

Genomics and Bioinformatics Laboratory Department of Biology University of York Heslington York UK

Inflammatory Skin Disease Group Leeds Institute of Rheumatic and Musculoskeletal Medicine School of Medicine Faculty of Medicine and Health University of Leeds Leeds UK

Maltepe University Faculty of Medicine Istanbul Turkiye

MRC University of Glasgow Centre for Virus Research 464 Bearsden Road Glasgow UK

School of Medicine University of Leeds Leeds UK

Virology Unit Department of Medical Biotechnologies University of Siena 53100 Siena Italy

Virus Host Interaction Team Skin Research Centre York Biomedical Research Institute Hull York Medical School University of York York UK

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