Lyme disease caused by the spirochete Borrelia burgdorferi is the most prevalent tick-borne disease in the United States and Europe. It is a systemic and chronic disease with involvement of the skin, nerves, heart, and joints. Antibiotic therapy may be ineffective, especially in patients with chronic debilitating lyme arthritis. The development of approaches to successful disease prevention requires an understanding of the borrelial virulence determinants involved in the pathogenesis of Lyme disease. Despite the fact that B. burgdorferi can be cultured readily in complex media in a microaerophilic environment, very little is known about tahe physiology of the spirochete. The long-term objectives of this project focus on the involvement of oxygen (O2) in the physiology of B. burgdorferi. Preliminary studies have shown that B. burgdorferi consumes O2 and grows in a microaerophilic atmosphere of 4% O2 but not in strictly aerobic or anaerobic environments. The spirochete produces a soluble hemolysin that is activated by a reducing agent such as cysteine. Infectivity for neonatal Lewis rats is maintained through 20 serial passages when B. burgdorferi is cultured in vitro in an atmosphere of 4% O2 but not in ambient O2 (approximately 9% O2). The proposed specific aims are based on the central hypothesis that O2 is a controlling factor in the pathogenicity of B. burgdorferi.
For Aim 1 it is hypothesized that B. burgdorferi possesses oxidative catabolic enzymes that are sensitive to changes in the dissolved O2 concentration (DOC). Metabolic endproducts, oxidizable substrates, and central pathways for substrate degradation will be analyzed to characterize athe catabolic metabolism of B. burgdorferi. Inactivation of O2-sensitive enzymes which may be related to the loss of infectivity in ambient O2 will be detected by shifts in endproducts at varying DOCs.
For Aim 2 it is hypothesized that O2 consumption generates intracellular toxic O2 intermediates, necessitating athe differential production of enzymatic defenses in response to O2. In order to investigate the O2 requirement in the face of O2 toxicity, the O2-consuming reactions in the cell and the expression of superoxide dismutase, catalase, and peroxidase will be analyzed. The levels of these defenses in infective and noninfective borreliae will be correlated with their susceptibility to killing by toxic O2 intermediates.
For Aim 3 it is hypothesized that changes in the DOC modify the expression of proteins in B. burgdorferi, some of which may be virulence determinants. If the modification is due to mutation or loss of genes, then the infective phenotype will not be restored upon passage of noninfective strains in 4% O2. An O2-stress response as well as the induction and/or repression of proteins and antigens in low and high DOCs will be evaluated to determine the role of O2 as an environmental stimulus. These studies are fundamental to our understanding of the physiology of B. burgdorferi and will lead to the eventual identification of virulence determinants involved in the pathogenesis of Lyme disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Bacteriology and Mycology Subcommittee 2 (BM)
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University of Louisville
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