Date of Award

January 2021

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Francis Y. Lee

Second Advisor

Jonathan Grauer

Abstract

Bone and joint infections caused by methicillin-resistant Staphylococcus aureus (MRSA) require a novel treatment modality due to high rates of recurrence and cartilage degradation. The primary objective of this study was to elucidate the inflammatory pathology of septic arthritis to improve the clinical care of musculoskeletal infections. A transcriptome dataset of MRSA infection was constructed and validated in a murine septic arthritis model of MRSA infection, as well as MRSA-infected human synovial and cartilage tissues. The therapeutic effect of vancomycin, influence of killed MRSA, and benefits of rifampin- and NLRP3 inflammasome inhibitor-loaded, locally applied hydrogels in reducing MRSA bioburden and chondrocyte damage in conjunction with systemic vancomycin treatment were verified in vitro and in vivo. Transcriptome analysis showed that IL-1β expression, which is mediated by the NLRP3 inflammasome, played a harmful role in MRSA-induced septic arthritis. Mono-therapeutic vancomycin administration is effective in septic arthritis but limited by the survival of MRSA within the intracellular environment and persistence of intraarticular inflammation even after MRSA eradication. MRSA-infected mice treated with vancomycin developed bone and joint damage due to the persistence of inflammation. Dual hydrogel therapy containing rifampin and a NLRP3 inflammasome inhibitor yielded better outcomes than systemic vancomycin treatment alone, as evidenced by the reduction of intraarticular cytokine expression and chondrocyte damage. The current study’s findings suggest that combined treatment with local rifampin and OLT1177-containing hydrogels and systemic vancomycin therapy is effective against MRSA-induced septic arthritis. This hydrogel-based local treatment has the potential to contribute to a paradigm shift in the therapeutic approach to MRSA-induced septic arthritis and osteomyelitis.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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