This highly productive Program seeks support to continue studies investigating Lyme disease pathogenesis and protective immunity, using a number of cellular, molecular, genetic, and immunological approaches with a well-characterized mouse model. The Program consist of five interactive projects and three supporting cores: Project #1 will investigate host immunity to Ixodes scapularis ticks and evaluate the effect of induced tick immunity upon infectivity, transmission and surface antigen expression of tick-borne Borrelia burgdorferi. Project #2, through studies in vitro, ex vivo and in situ, will provide a comprehensive picture of the functional integrity of phagocytes in the B. burgdorferi-infected host. Project #3 will study the regulation of differential B. burgdorferi gene expression in the tick vector, culture and the mammalian host. Project #4 will determine whether B. burgdorferi, with variable outer surface proteins that do not bind protective antibody and therefore resist elimination by the host, preferentially survive within infected mice and humans, thereby contributing to the pathogenesis of Lyme disease. Project #5 is investigating the pathogenesis of Lyme borreliosis in a mouse model. This project is financially supported outside the context of this POl, but is integrally related to the POl effort. It is therefore included as a project (without request for additional funding) to provide the reviewers a global perspective of our program. Core A will support the administration of this Program. Core B will provide standardized media, animal inoculation, immunization, tissue collection, histology and professional pathology services to support projects of this Program.