Lyme disease is the most prevalent arthropod borne infection in the United States. The disease is caused by the spirochete Borrelia burgdorferi, which is transmitted to humans via infected Ixodes ticks. Lyme disease is a multiple systemic disorder with various clinical manifestations including erythema migrans, arthritis, musculoskeletal and neurological manifestations. In the United States, approximately 60% of untreated patients develop Lyme arthritis. After deposition in the skin by a tick bite, spirochetes traverse the intracellular matrix, penetrate the vascular endothelial cell lining, and are disseminated to target tissues. However, the mechanisms involved in this invasive process are largely unknown. While motility and chemotaxis are critical for many pathogenic organisms to colonize and/or cause disease, the role of these processes in B. burgdorferi-mediated pathogenesis has not been determined.Three aims will test the hypothesis that chemotaxis and motility are critical for B. burgdorferi-induced pathogenesis. Aim 1: mutants in specific chemotaxis genes (e.g., cheX and cheYS) will be constructed in an infectious B. burgdorferi strain. Phenotypes of these mutants will be characterized with respect to motility and chemotaxis. To ensure that a given phenotype is not attributed to secondary alterations, mutated genes will be complemented. Aim 2: the hypothesis that motility and chemotaxis are critical for B. burgdorferi pathogenesis will be tested using a mouse model of Lyme disease. We predict that mutants defective in chemotaxis and motility will be less virulent than the parental strain. Aim 3: we will test the hypothesis that chemotaxis/motility is responsible for B. burgdorferi migration from tick midgut to salivary glands following a blood meal. Wild type and mutant B. burgdorferi will be introduced into tick midguts by immersing ticks in spirochete-laden solutions. Following a blood meal on mice, the extent to which wild type and mutant B. burgdorferi have migrated from tick midguts to salivary glands will be determined. The results of all studies will provide critical information on the pathogenesis of Lyme disease and could provide the foundation for novel approaches to prevent Lyme disease including Lyme associated arthritis.