Lyme disease is caused by infection with the spirochete Borrelia burgdorferi. B. burgdorferi is maintained in nature through an enzootic cycle comprising a tick vector and vertebrate host. Transmission from the tick to the mammal and establishment of the mammalian infection require sensing external signals and responding by regulating programs of gene expression. This change in gene expression is predominantly mediated by the alternative sigma factor RpoS. The central hypothesis of this application is that RpoS is the principal transcriptional regulator controlling transmission to and infection of the mammalian host, and thus serves as the target of several regulatory mechanisms. We propose to dissect the mechanisms controlling rpoS expression and RpoS activity on downstream targets. Specifically, we hypothesize that a novel rpoS transcript has a distinct role in transmission and is processed by a recently identified endoribonuclease;the signaling molecule guanosine tetraphosphate, and associated regulatory proteins, globally affect RpoS-mediated transcription and translation throughout the enzootic cycle;and a small regulatory RNA affects sigma factor selectivity and activity. The long-term objective of this proposal is to understand th role and regulation of RpoS in tick-to-mammal transmission and disease pathogenesis, which will lead to improved diagnostic, prevention, and treatment strategies because RpoS is required for B. burgdorferi to cause Lyme disease;this is relevant to the mission of the agency to """"""""seek fundamental knowledge"""""""" for the sake of alleviating human disease. The following specific aims are proposed toward achieving this objective: 1) determine the role of, and processing mechanism for, the novel rpoS transcript;2) elucidate the targets and function of guanosine tetraphosphate during the enzootic cycle;and 3) characterize a small RNA that regulates sigma factor selectivity. Genetic, biochemical, transcriptomic, and proteomic approaches will be utilized to test these hypotheses. Specifically, genes encoding regulatory factors (or the production of regulatory factors) will be disrupted and/or fused to an inducible promoter to assay in vivo function in a tick-mouse model.

Public Health Relevance

Lyme disease is the most prevalent infection transmitted by arthropods in the United States, with almost 23,000 confirmed cases reported in 2010;the incidence in the top ten endemic states was 44.5 cases per 100,000 people. The bacterium Borrelia burgdorferi causes Lyme disease when it is transmitted to humans by the feeding of Ixodes ticks. This application proposes to understand the molecular mechanisms of B. burgdorferi transmission from ticks to mammals.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacterial Pathogenesis Study Section (BACP)
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Breen, Joseph J
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University of Montana
Schools of Arts and Sciences
United States
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Drecktrah, Dan; Hall, Laura S; Rescheneder, Philipp et al. (2018) The Stringent Response-Regulated sRNA Transcriptome of Borrelia burgdorferi. Front Cell Infect Microbiol 8:231
Drecktrah, Dan; Samuels, D Scott (2018) Genetic Manipulation of Borrelia Spp. Curr Top Microbiol Immunol 415:113-140
Anacker, Melissa L; Drecktrah, Dan; LeCoultre, Richard D et al. (2018) RNase III Processing of rRNA in the Lyme Disease Spirochete Borrelia burgdorferi. J Bacteriol 200:
Samuels, D Scott; Drecktrah, Dan; Hall, Laura S (2018) Genetic Transformation and Complementation. Methods Mol Biol 1690:183-200
Lybecker, Meghan C; Samuels, D Scott (2017) Small RNAs of Borrelia burgdorferi: Characterizing Functional Regulators in a Sea of sRNAs?. Yale J Biol Med 90:317-323
Samuels, D Scott; Samuels, Leah R N (2016) Gene Regulation During the Enzootic Cycle of the Lyme Disease Spirochete. For Immunopathol Dis Therap 7:205-212
Caimano, Melissa J; Drecktrah, Dan; Kung, Faith et al. (2016) Interaction of the Lyme disease spirochete with its tick vector. Cell Microbiol 18:919-27
Drecktrah, Dan; Lybecker, Meghan; Popitsch, Niko et al. (2015) The Borrelia burgdorferi RelA/SpoT Homolog and Stringent Response Regulate Survival in the Tick Vector and Global Gene Expression during Starvation. PLoS Pathog 11:e1005160
Drecktrah, Dan; Hall, Laura S; Hoon-Hanks, Laura L et al. (2013) An inverted repeat in the ospC operator is required for induction in Borrelia burgdorferi. PLoS One 8:e68799
Imai, Denise M; Samuels, D Scott; Feng, Sunlian et al. (2013) The early dissemination defect attributed to disruption of decorin-binding proteins is abolished in chronic murine Lyme borreliosis. Infect Immun 81:1663-73

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