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Sand fly saliva reprograms skin fibroblasts to enhance arbovirus infection
Yonca Keskek Turk1,2, Ailish McCafferty-Brown1,2, Liam Barningham1,2
1School of Medicine, University of Leeds, Leeds, UK.
Abstract:
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.
Insights
Sand fly saliva enhances Toscana virus (TOSV) infection by reprogramming skin fibroblasts, leading to amplified viral spread and disease. This reveals a critical role for skin cells in arbovirus pathogenesis.
Area of Science:
- Virology
- Immunology
- Public Health
Background:
- Arbovirus transmission by sand flies poses a significant public health threat.
- Early events in the skin following sand fly-borne viral transmission are not well understood.
- Toscana virus (TOSV) is a relevant arbovirus transmitted by sand flies.
Purpose of the Study:
- To investigate the early skin events during natural Toscana virus transmission by sand flies.
- To elucidate the role of sand fly saliva in modulating host response and viral pathogenesis.
- To establish a mouse model that mimics natural sand fly-mediated arbovirus transmission.
Main Methods:
- Development of a mouse model for Toscana virus infection using sand fly salivary factors.
- Analysis of infected cell types in the skin post-transmission.
- Assessment of viral replication, spread, and clinical manifestations.
- Investigation of cellular reprogramming in response to sand fly saliva.
Main Results:
- Sand fly saliva from two genera significantly enhanced TOSV infection, neurological signs, and joint inflammation.
- Dermal macrophages and fibroblasts were the primary infected cells in the skin.
- Only fibroblasts produced infectious viral particles after saliva exposure.
- Sand fly saliva induced a wound-healing state in fibroblasts, promoting viral replication and systemic spread.
Conclusions:
- Skin fibroblasts are key determinants of host susceptibility to TOSV infection.
- Sand fly saliva actively remodels the skin, exacerbating viral pathogenesis.
- This study redefines the skin's role in sand fly-transmitted arbovirus infections.
- Identified fibroblasts and saliva-induced reprogramming as potential targets for therapeutic and vaccine development.
