Abstract

Borrelia burgdorferi (Bb), transmitted through tick vectors, induces Lyme arthritis (LA), with disease progression intimately correlated with host genetic characteristics. Laboratory investigations have demonstrated marked disparities in infection responses among distinct mouse strains: C57BL/6 mice have mild arthritis and rapid tissue repair, whereas C3H mice exhibit severe arthritic manifestations. Comparing these strains has helped identify genetic and immune factors important for arthritis development. In this study, female C57BL/6 and C3H mice were inoculated with Bb via bilateral footpad injection. Disease progression was evaluated through multidimensional parameters, including joint swelling measurements, radiographic examinations, and histopathological analyses at acute (14 days) and chronic (56 days) phases. RNA-seq of joint tissue, combined with single-sample gene set enrichment analysis, immune deconvolution, and multi-omics enrichment revealed strain-divergent signatures. The experimental data unveiled strain-specific immune response patterns: C3H mice exhibited persistent inflammatory responses characterized by heightened complement system activation, sustained inflammatory mediator expression, and prolonged inflammasome activity. C57BL/6 mice maintained relatively stable inflammatory mediator levels and immune homeostasis. Transcriptomic analysis revealed 2,183 (C3H) and 439 (C57BL/6) differentially expressed genes on day 14 post-infection, encompassing processes related to immune cell recruitment, cytokine networks, and complement activation. These findings illuminate the regulatory role of host genetic background in temporal characteristics of immune responses, providing novel molecular insights into differential susceptibility to LA.