Lyme disease is the most prevalent tick-borne disease in the United States. Borrelia burgdorferi (Bb), the causative agent, is highly motile and can traverse complex environments inside mammalian and arthropod hosts during its infectious cycle. The central hypothesis of this application is that the motility and chemotaxis of Bb constitute a unique paradigm and play a pivotal role in the host-vector cycle as well as in the disease process, e.g., dissemination, tissue tropism, and immune evasion. During our last funding period, several unique aspects about Bb motility and chemotaxis were unveiled. In collaboration with several other groups, we have pushed Bb motility research to the forefront, and now Bb has emerged as a paradigm for in-depth understanding of spirochete motility and chemotaxis. In this renewal application, a comprehensive study will be carried out to elucidate the molecular mechanisms that account for the unique aspects that we have observed as well as their links to Bb pathogenicity. Bb has 7-11 internally localized periplasmic flagella (PFs) nea the cell poles. They form a distinct ribbon wrapping around the cell cylinder, which have both skeletal and motility functions. This unique arrangement and function have not been reported in any other flagellated bacteria.
Aim 1 will define the molecular mechanism that controls the number and placement of PFs and determine how this control mechanism affects the virulence of Bb. As an enzootic pathogen, Bb has two different chemosensory pathways. It has been hypothesized that these two pathways function in different hosts during the infectious cycle, e.g., one in mammals and the other in ticks.
Aim 2 will decipher the unique aspect of chemotaxis and its role in the enzootic cycle of Bb. Bb is highly motile and outruns (>10-fold faster) host immune cells in mouse dermis. We hypothesize that this ability allows Bb to rapidly disseminate through dense skin tissue ahead of the cellular immune responses and then to disseminate to distal organs in mammals.
Aim 3 will test our hypothesis by analyzing two motility and chemotaxis mutants in mice using recently developed live-imaging techniques. All of the studies proposed in this renewal are novel and have not been carried out in any spirochetes. Completion of these studies will lead to a new level of molecular analysis of Bb motility and chemotaxis as well as an understanding of their precise roles in the pathogenesis of Lyme disease. In addition, the fundamental knowledge to be gained here is high-impact and could aid in the understanding of the unique motility in other pathogenic spirochetes.

Public Health Relevance

The pathogenic spirochetes, such as the Lyme disease spirochete Borrelia burgdorferi, are highly motile and invasive. The goal of this project is to understand the basic biology of spirochete motility and chemotaxis, and their roles in the pathogenesis of the diseases. The obtained results may lead to new means of disease prevention and treatment.

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)
Program Officer
Perdue, Samuel S
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State University of New York at Buffalo
Schools of Dentistry
United States
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Curtis, Michael W; Hahn, Beth L; Zhang, Kai et al. (2018) Characterization of Stress and Innate Immunity Resistance of Wild-Type and ?p66 Borrelia burgdorferi. Infect Immun 86:
Kurniyati, Kurni; Liu, Jun; Zhang, Jing-Ren et al. (2018) A pleiotropic role of FlaG in regulating the cell morphogenesis and flagellar homeostasis at the cell poles of Treponema denticola. Cell Microbiol :e12886
Kurniyati, Kurni; Kelly, John F; Vinogradov, Evgeny et al. (2017) A novel glycan modifies the flagellar filament proteins of the oral bacterium Treponema denticola. Mol Microbiol 103:67-85
Miller, Michael R; Miller, Kelly A; Bian, Jiang et al. (2016) Spirochaete flagella hook proteins self-catalyse a lysinoalanine covalent crosslink for motility. Nat Microbiol 1:16134
Zhang, Kai; Bian, Jiang; Deng, Yijie et al. (2016) Lyme disease spirochaete Borrelia burgdorferi does not require thiamin. Nat Microbiol 2:16213
Zhang, Kai; Liu, Jun; Charon, Nyles W et al. (2016) Hypothetical Protein BB0569 Is Essential for Chemotaxis of the Lyme Disease Spirochete Borrelia burgdorferi. J Bacteriol 198:664-72
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Li, Chen; Kurniyati; Hu, Bo et al. (2012) Abrogation of neuraminidase reduces biofilm formation, capsule biosynthesis, and virulence of Porphyromonas gingivalis. Infect Immun 80:3-13
Sze, Ching Wooen; Zhang, Kai; Kariu, Toru et al. (2012) Borrelia burgdorferi needs chemotaxis to establish infection in mammals and to accomplish its enzootic cycle. Infect Immun 80:2485-92

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