The natural release of unusual peptidoglycan fragments drives persistent Lyme disease symptoms in susceptible hosts

ABSTRACT Lyme disease is the most reported vector-borne disease in the Northern Hemisphere. Lyme disease is caused by the spirochetal bacterium¾Borrelia burgdorferi¾an unusual pathogen in that it is capable of causing severe disease, despite lacking any recognizable virulence factors. Prompt therapy is often affective, but many patients may still experience severe symptoms, chiefly Lyme arthritis. The reason(s) for persistent symptoms is poorly understood and the most debated topic in the field. The lead investigator of this proposal discovered that B. burgdorferi sheds ~45% of its peptidoglycan (PG)—the essential component of the bacterial cell-wall—from inside the cell, into its environment. B. burgdorferi PG can be detected in the synovial fluid of Lyme arthritis patients' months after oral and/or intravenous antibiotics. Experimental animal studies have shown that purified B. burgdorferi PG alone, is capable of causing arthritis. We have shown that the chemical constituents of B. burgdorferi PG are unlike any on the planet and real-time tracking studies indicate that these unique features are associated with extended dwell times in discrete organs. Taken together, we hypothesize that the natural release of unique B. burgdorferi PG fragments is responsible for driving Lyme arthritis, post-therapy, in susceptible mammals, but we can target lingering fragments for therapeutic purposes. This proposal will critically assess 1) what exactly is being released and what persists; 2) where and how the material persists; 3) the relationship between Borreliae PG chemistry and persistent disease; 4) host factors that may contribute to PG- induced arthritis; and 5) if targeted monoclonal antibody therapy is viable approach to treat patients suffering from Lyme arthritis. Our studies will fill critical knowledge gaps in what is driving patient symptomology after antibiotic therapy and may lead to new ways to treat patients when conventional options have failed.