Lyme borreliosis is a prevalent vector-borne disease in the United States, Europe, and parts of Asia, caused by the bacterial pathogen Borrelia burgdorferi. The infection can be difficult to diagnose, and a human vaccine is currently unavailable. The application will study how BBA57 - a unique borrelial gene product and newly identified virulence determinant of unknown function - contributes to multiple aspects of microbial infectivity and pathogenesis and also assess its efficacy in generating protective host immunity against infection. Although many bacterial pathogens have evolved measures to limit host microbicidal responses, relatively little is known about how B. burgdorferi evade innate immunity as they transmit to mammalian hosts. Based on our published and new preliminary data, we hypothesize that BBA57, an in-vivo induced, surface-exposed outer membrane protein, facilitates spirochete defense against specific host innate immune responses and that the antigen induces production of neutrophil-recruiting chemokines in joint cells, which triggers arthritis. Upon successful completion of the proposed work, we will be able to demonstrate that BBA57 represents, to the best of our knowledge, the first example of a B. burgdorferi protein that confers resistance to specific antimicrobial peptides (AMPs), thereby promoting establishment of early B. burgdorferi infection in murine hosts. We have three major goals. First, we will examine how BBA57 contributes to spirochete AMP resistance during early infection. Second, we will identify the joint cell type(s) that are responsible for BBA57-mediated chemokine responses critical for arthritis. Finally, as BBA57 is also dramatically produced in ticks, we will explore the role of the protein in perpetuating the vector phases of the borrelial lfe cycle, including tick-to-mouse transmission, and based on our preliminary immunization data, we will assess its potential as a new candidate antigen for generation of protective host immunity. In sum, these studies will contribute to better understanding the infectivity and pathogenesis of B. burgdorferi and help in the development of novel preventive and therapeutic measures to combat infection.