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Title: A small intergenic region of lp17 is required for evasion of adaptive immunity and induction of disease pathology by the Lyme disease spirochete

Author
item CASSELLI, TIMOTHY - Washington State University
item CROWLEY, MICHAEL - Washington State University
item Highland, Margaret
item TOURAND, YVONNE - Medical University Of North Dakota
item BANKHEAD, TROY - Washington State University

Submitted to: Cellular Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/30/2018
Publication Date: 4/3/2019
Citation: Casselli, T., Crowley, M.A., Highland, M.A., Tourand, Y., Bankhead, T. 2019. A small intergenic region of lp17 is required for evasion of adaptive immunity and induction of disease pathology by the Lyme disease spirochete. Cellular Microbiology. 21(7):e13029. https://doi.org/10.1111/cmi.13029.
DOI: https://doi.org/10.1111/cmi.13029

Interpretive Summary: This is collaborative research with Washington State University investigating regions within the genome of Borrelia burgdorferi that allow for colonization and disease in susceptible hosts. B. burgdorferi is the causative agent of Lyme disease, serious disease that impacts both humans and animals (cattle, dogs), causing long term health consequences including carditis and arthritis. By using the mouse as a model and molecular techniques to remove specific regions of the genome, a segment of the genome was identified that is associated with colonization and disease. By removing this specific segment of the genome, located on the linear plasmid lp17, tissue colonization was impaired and there was a significant decrease in carditis and arthritis. The long term impact/outcome of this research would be in vaccine development or targeted treatments to diminish this pathogen's ability to colonize susceptible hosts.

Technical Abstract: The causative agent of Lyme disease, Borrelia burgdorferi, possesses a segmented genome comprised of a single linear chromosome and upwards of 23 linear and circular plasmids. Many of the plasmids are routinely lost during in vitro culture, and their requirements during mammalian infection have been elucidated. Other plasmids, including the linear plasmid lp17, are maintained with higher fidelity in vitro and therefore their involvements during mammalian infection are not well understood. Identification of bacterial plasmid-borne genetic factors required for immune evasion, tissue colonization, and induction of disease pathology could provide targets for novel therapeutics and vaccines. In this study, the effects of mutating a ~4.7 kb fragment of linear plasmid lp17 were characterized using a mouse model of infection and disease. Although mutant strains lacking the ORFs bbd01-bbd07 showed no deficiency in establishing initial infection or disseminating to the bloodstream of mice, colonization of peripheral tissues was significantly impaired. The deficiency in tissue colonization was alleviated in SCID mice, implicating a role for this region of lp17 in adaptive immune evasion. The tissue colonization defect could be fully attributed to a 317 bp region containing the bbd07 ORF and upstream sequence, however heterologous expression of bbd07 was not sufficient to rescue the phenotype. Impaired tissue colonization was correlated with decreased induction of carditis and arthritis. This study reveals for the first time the contribution of lp17-encoded genes to colonization of joint and heart tissues, and the associated disease pathology caused by this important pathogen.