Date of Award

May 2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Archana Dhasarathy

Second Advisor

Catherine A. Brissette

Abstract

Lyme arthritis (LA), a manifestation of Lyme disease, is triggered by the spirochetal bacterium Borrelia burgdorferi (Bb), which is transmitted through the bite of the Ixodes tick. Although most instances of Lyme arthritis can be successfully managed by antibiotics, around 10% of cases persist after antibiotic treatment, a phenomenon known as post-treatment LA. In the absence of an active infection, Post-treatment LA can persist several months to multiple years after antibiotic treatment. Although the exact cause of post-treatment LA is unknown, symptoms such as joint swelling and pain are thought to be driven by immunological factors such as the production of large amounts of proinflammatory cytokines and chemokines by synoviocytes in response to interferons. After infection with Bb, synoviocytes, specialized cells in the lining of the synovial membrane of joints, tendons and bursae that normally produce synovial fluid become highly proliferative immune effector cells capable of perpetuating the symptoms of LA in the absence of active infection. We hypothesized that short-term infection with Bb epigenetically “primes” synoviocytes to become more sensitive to future inflammatory stimuli such as high levels of Type I Interferons (IFNs) which has been shown to drive LA pathology. To test our hypothesis, we established a long-term cell culture model using SW982 synovial sarcoma cells. We cultured SW982 cells with Bb at early passage, and following bacterial clearance, grew them for an additional 8 passages without Bb, alongside naïve, untreated cells. Interferon alpha 2 A (IFN2A) treatment of the cells resulted in hyper-activation of a distinct subset of genes in the Bb primed cells relative to control. Further, we identified increased chromatin accessibility and increased amounts of the enhancer histone mark monomethyl lysine 4 on histone H3 (H3K4me1) at the transcription start site of specific memory genes of cells primed with Bb relative to naïve cells. We present evidence that acquisition of H3K4me1 at transcription start sites is likely established at a subset of genes shortly after initial Bb treatment and is maintained for up to 10 passages or roughly 20 generations post bacterial clearance. Lysine Demethylase 5A (KDM5A), which removes two methyl groups from H3K4me3 at active genes, and Lysine Methyltransferase C (KMT2C) which maintains the resulting mono-methylated H3K4 are paramount to establishment and maintenance of H3K4me1. Taken together, our work suggests that Bb primes genes to generate a transcriptional memory response that might be causative for post-infectious LA.

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