Cellular processing and role of a surface antigen in borrelial pathogenesis

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DESCRIPTION (provided by applicant): Lyme disease, a prevalent arthropod-borne disease, results from infection with the bacterial pathogen Borrelia burgdorferi. The microbe survives in nature through an intricate enzootic cycle involving Ixodes ticks and mammals. During feeding, infected ticks can transmit B. burgdorferi to the host dermis, from where the spirochete disseminates to a number of internal organs including the joints, heart and nervous system, causing severe inflammatory disorders collectively known as Lyme disease or Lyme borreliosis. Severe infiltration of certain inflammatory cells is a major feature of Lyme borreliosis that contributes to pathological damage in the infected organs. Previous studies have demonstrated that B. burgdorferi possesses potent cytokine-stimulating properties and that spirochete lipoproteins induce the production of pro-inflammatory cytokines. Our recent studies involving B. burgdorferi gene products showed that the antigen Lmp1, annotated as surface-located membrane protein 1, is a virulence determinant of the Lyme disease pathogen. Although Lmp1 plays important roles in B. burgdorferi virulence, its function in the pathogen biology or its contribution in spirochete infectivity remains unknown. We now discovered that a fraction of native full-length (128 kDa) Lmp1 protein is processed into distinct lower-molecular weight polypeptides in B. burgdorferi and that infection with lmp1 mutants result in less severe Lyme arthritis compared to wild type spirochetes. The goal of our current proposal is to better understand the processing mechanism of native Lmp1 and study the potential role of Lmp1 as a molecular trigger of host inflammatory disorders. This study will shed new light on the mechanism of spirochete pathogenesis and may also help the development of novel preventive measures against Lyme disease.