Transcriptomic response to Borrelia afzelii infection in the skin of wild bank voles

Bank voles are one of the main reservoirs of tick-transmitted spirochete Borrelia afzelii, a causative agent of Lyme disease in humans in Europe. How the immune system deals with infection at the site of entry, that is, the skin, has not been explored in this species. Here, we used RNA sequencing to explore the transcriptomic response in the ear skin of wild bank voles infected with B. afzelii. We identified 54 differentially expressed genes, of which 37 showed upregulation, and 17 showed downregulation in infected voles compared to uninfected ones. Weighted gene co-expression network analysis identified five gene modules, which were positively or negatively correlated with infection status. Enrichment analysis revealed numerous biological processes and pathways related to immune response, extracellular matrix organization, metabolism, energy production, gene expression, and cell cycle regulation. Among immunity-related genes, pathways related to B-cell activity and antibody production were particularly upregulated. However, we found that the pro-inflammatory response is suppressed compared to that reported in humans, and we identified changes in the expression of genes related to the extracellular matrix, whose products are bound and colonized by Borrelia. These findings indicate a complex response of bank voles to B. afzelii infection and provide insight into the molecular processes associated with infection in a natural reservoir host.IMPORTANCELyme disease is a common infectious disease in Europe and North America caused by Borrelia burgdorferi sensu lato spirochetes, which are transmitted through tick bites. While the infection can lead to severe symptoms in humans, including fatigue, fever, joint pain, and neurological disorders, natural reservoir hosts such as rodents typically remain asymptomatic, providing an important model for uncovering the molecular basis of infection tolerance. By comparing gene expression differences between Borrelia-infected and -uninfected individuals of a wild rodent species, the bank vole, we identified molecular pathways involved in the early response at the site of infection, the skin. Our findings revealed a reduced pro-inflammatory response, enhanced adaptive immune activation, particularly involving B-cell-mediated processes, and changes in extracellular matrix organization. These results provide insight into the immune strategy of reservoir hosts and may help explain why Lyme disease causes more severe symptoms in humans.