Modeling Infection-Associated Chronic Illness: Murine Borrelia burgdorferi-Driven Connective Tissue Alterations and MAESTRO Clinical Correlates 2260529

Abstract Introduction Borrelia burgdorferi (Bb), the bacterium that causes Lyme disease, is linked to chronic illness in an estimated two million Americans. The mechanisms driving these persistent symptoms remain unclear, particularly the balance between immune- and pathogen-mediated processes. This project combines a murine Bb infection model with data from the MAESTRO clinical study to define immune responses, downstream effects, and their translational relevance. Methods C57BL/6 and C3H/HeJ mice of different ages were infected with Borrelia burgdorferi and followed longitudinally via in vivo imaging and tissue analyses. Ex vivo nonlinear imaging, histology, and in vitro assays using blood and tissue-derived cells were performed. Human data from the MAESTRO study, including medical history, symptom reports, and clinical evaluations, were incorporated for translational analysis. Results Overall infection level correlated with higher bacterial burden in the tail and increased tail flexibility - a hypermobile phenotype observed only in infected C3H mice. Significant Bb filamentation and elevated NAD(P)H per bacterial unit occurred in B6 but not C3H mice, while FAD levels showed a linear trend across strain and age. Shorter Bb forms correlated with larger, metabolically active macrophages displaying lower optical redox ratios, and evidence of phagocytosis was greater near shorter Bb. Mast cell distribution, degranulation, and directionality varied by strain and age, correlating with changes in collagen II intensity. Human MAESTRO data similarly revealed increased prevalence of hypermobility, mast cell disorders, and related symptom burden among chronically ill cohorts. Conclusion Findings indicate that persistent Borrelia infection promotes mast cell—mediated collagen II degradation and connective tissue hypermobility, offering mechanistic insight and a model for therapeutic and infectious disease studies. Funding Source NIH, Emily and Malcolm Fairbairn Foundation Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)