Principal Research Scientist MIT Cambridge, Massachusetts, United States
Introduction/Rationale: 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.
