Unraveling the Immunopathology of Infection-Associated Chronic Illnesses: Sex Differences and Predictive Diagnostics 2267580

Abstract

Abstract Introduction Infection-associated chronic illnesses (IACI) following Borrelia burgdorferi (Bb) or SARS-CoV2 infection lack objective diagnostics and can induce a multitude of co-morbid conditions including connective tissue disorders which were previously considered to be genetic. We hypothesize that host immune polarization dictates pathology. We employ a translational approach, combining a novel long-term murine model of Bb infection with the deeply phenotyped MAESTRO human IACI cohort to dissect these immunopathologies. Methods We established a 2-year Bb infection model in C3H and BL/6 mice, quantifying joint hypermobility. Novel label-free 3D metabolic imaging visualized the host-pathogen interface in situ. In the parallel MAESTRO clinical study, human IACI patients underwent multi-modal phenotyping including neurocognitive assessments, hypermobility assessments, incorporated with survey data and deep biological sample profiling. Results Long-term Bb infection induced systemic hypermobility only in C3H mice, driven by a maladaptive, mast cell-dominant response causing targeted degradation of Type II collagen. This links an allergic process to tissue damage. In tolerant B6 mice, a macrophage-dominant response drove Bb into an extremely elongated morphology as a novel immune evasion strategy. The MAESTRO cohort mirrors these findings, revealing patient endotypes with mast cell activation, hypermobility, neuroinflammation, and reproductive immunology dysfunction. Conclusion Host immune polarization dictates chronic illness trajectories associated with infection. A maladaptive, mast cell-driven allergic response can directly induce a systemic connective tissue disorder even in the absence of genetic risk factors typically associated with such diseases, offering a new paradigm for infection-induced hypermobility. This work mechanistically links diverse IACI symptoms and supports a therapeutic shift of targeted immunomodulation. Funding Source Emily and Malcolm Fairbairn, MLSC, NIH NIAID RO1 AI 178713-01 Topic Categories Immune Mechanisms of Human Disease (HUM)