CD1-Mediated Immunity in Lyme Disease

Yale University, New Haven CT

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Abstract

DESCRIPTION (Taken from the applicant's abstract): Lyme disease is a multisystem disorder caused by infection with the tick-borne spirochete, Borrelia burgdorfer. The disease occurs in stages that reflect the biology of the spirochete as it adapts from survival in the tick to the more hostile environment of the mammal. B. burgdorferi contains an abundant array of highly immunogenic outer membrane lipoproteins (Osps) that are differentially expressed throughout the spirochete lifecycle. Lipoproteins incite inflammation and are believed to be the principal spirochete component causing disease. Lipoproteins can also elicit protective humoral immunity but current vaccines fail to elicit long-lived immunity. This research proposal is based on findings that absence of CD1d, a nonclassical antigen presenting molecule that binds lipid Ag, renders mice susceptible to B. burgdorferi infection and disease. Pathology correlates with high-titer T-dependent antibody responses to spirochete lipoproteins, including lipoproteins only transiently expressed by spirochetes establishing infection in the host. They hypothesize that CDld functions to facilitate the elimination of spirochetes and their disease-inciting lipoproteins by potentiating innate immune mechanisms. This research proposal seeks to 1) understand the molecular and cellular mechanisms by which CD1d-mediated immunity controls spirochetal pathogens; 2) determine whether blocking CDld will enhance the duration of lipoprotein vaccine-induced immunity; 3) examine the ways in which spirochetes infecting CDld-deficient mice adapt to persist in the face of an altered mammalian host defense; and 4) use the adaptive immune response that evolves in the absence of CDld to identify key lipoproteins necessary for tick-borne spirochetes to infect and disseminate in the mammalian host. The completion of these studies, which evaluate both mammalian host defense and host adaptation of spirochetes, is intended to allow for broad insights into how CDld acts to bridge innate and adaptive immunity, and its role in defense against pathogens and modulation of innate immunity