Lyme disease is a multisystem illness caused by infection with the spirochete Borrelia burgdorferi and it is the leading vector-borne disease in the United States. Our current work addresses the following areas in Lyme disease: development of new tests and biomarkers for infection, investigation of persistence of infection with B. burgdorferi in humans, and investigation of the role of immune response in Lyme disease and post treatment Lyme disease syndrome (PTLDS). One of the main problems in Lyme diagnosis has been the lack of highly specific and sensitive assays for B. burgdorferi and the lack of a test that could be used to assess response to therapy. Such assays should greatly facilitate the accurate diagnosis of Lyme disease and assessment of response to therapy in individual patients. Recent studies have shown that B. burgdorferi may persist in animals after antibiotic therapy and can be detected by using the natural tick vector (Ixodes scapularis) to acquire the organism through feeding. Whether this occurs in humans is unknown. We have completed a phase I study to investigate the utility of this approach for identifying persistence of B. burgdorferi in treated human Lyme disease, and are performing the phase 2 study. Inflammatory innate immune responses are critical in the control of early disseminated infection, while adaptive immune responses are vitally important, particularly the humoral immune response, in controlling spirochete levels in tissues and resolution of Lyme arthritis in animal models. We are examining the antibody response to immunogenically dominant antigens of B. burgdorferi in PTLDS patients and controls. Further investigation of the anti-borrelia immune response may help in elucidating the pathogenic mechanism of PTLDS and yield important information for future approaches to diagnosis and treatment. We have characterized the gene expression patterns in skin biopsies from individuals with EM, to learn about the human host response at the site of the infection. We are also investigating the immunological response in neuroborreliosis. Results from these studies give us a window into the fundamental biology of the infection.