Lyme disease is an important public health problem in the US. This emerging disease is underdiagnosed, and the late stages of Lyme disease are difficult to treat. The causative agent Borrelia burgdorferi (Bb) is maintained in a complex enzootic cycle involving its arthropod vector (Ixodes ticks) and a rodent mammalian host. Bb must dramatic alters its surface proteins in order to adapt to two markedly different host environments during tick feeding. Previously, we and others have established that the RpoN-RpoS pathway functions as a major mechanism underlying differential gene expression during the spirochete's enzootic cycle. The goal of this application is to fill in the major gap in the understanding of this essential pathway, that is, how multiple signals and regulators coordinately activate / regulate this pathway. Our preliminary findings support the following hypotheses, which will be tested in three Specific Aims: 1) This pathway connects Bb metabolism and virulence. 2) Acetylation plays an important role in the activation of this pathway and in the enzootic cycle of Bb. 3) the second messenger c-di-GMP modulates this pathway via a new c-di-GMP effector. This is a collaborative project including four experienced scientists with expertise in Bb gene regulation (Yang; PI), bacterial acetylation (Wolfe), Bb physiology (Gherardini), and c-di-GMP (Gomelsky). Outcomes of the work will reveal how Bb has evolved to connect metabolism and virulence and how acetylation modulates differential gene expression during the enzootic cycle of Bb. This work will also reveal a novel role of c-di-GMP in host adaptation of vector-borne pathogens. Our proposal will fill a major gap in our understanding of how Bb adapts to both arthropod and mammalian hosts. Outcomes of this work also will set a foundation for developing strategies to block the enzootic cycle of Bb, thus limiting its ability to cause human disease.

Public Health Relevance

Outcomes of this work will elucidate the complex signal sensing mechanisms of the RpoN-RpoS pathway, which will fill a major gap in our understanding of Bb host adaptation. These findings will not only allow us to gain insight into host adaptation of the Lyme disease pathogen, it will also form a basis for developing strategies to block the enzootic cycle of vector-borne bacterial pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083640-09
Application #
9463750
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Ilias, Maliha R
Project Start
2009-07-01
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Zhang, Jun-Jie; Hu, Wei-Lin; Yang, Youyun et al. (2018) The sigma factor ?54 is required for the long-term survival of Leptospira biflexa in water. Mol Microbiol :
Zhang, Jun-Jie; Chen, Tong; Yang, Youyun et al. (2018) Positive and Negative Regulation of Glycerol Utilization by the c-di-GMP Binding Protein PlzA in Borrelia burgdorferi. J Bacteriol 200:
Yang, Youyun; Wolfe, Alan; Yang, X Frank (2018) Identification of Acetylated Proteins in Borrelia burgdorferi. Methods Mol Biol 1690:177-182
Filippova, Ekaterina V; Zemaitaitis, Bozena; Aung, Theint et al. (2018) Structural Basis for DNA Recognition by the Two-Component Response Regulator RcsB. MBio 9:
Chen, Tong; Xiang, Xuwu; Xu, Haijun et al. (2018) LtpA, a CdnL-type CarD regulator, is important for the enzootic cycle of the Lyme disease pathogen. Emerg Microbes Infect 7:126
Xiang, Xuwu; Yang, Youyun; Du, Jimei et al. (2017) Investigation of ospC Expression Variation among Borrelia burgdorferi Strains. Front Cell Infect Microbiol 7:131
Filippova, Ekaterina V; Wawrzak, Zdzislaw; Ruan, Jiapeng et al. (2016) Crystal structure of nonphosphorylated receiver domain of the stress response regulator RcsB from Escherichia coli. Protein Sci 25:2216-2224
Ye, Meiping; Sharma, Kavita; Thakur, Meghna et al. (2016) HtrA, a Temperature- and Stationary Phase-Activated Protease Involved in Maturation of a Key Microbial Virulence Determinant, Facilitates Borrelia burgdorferi Infection in Mammalian Hosts. Infect Immun 84:2372-2381
Yin, Yanping; Yang, Youyun; Xiang, Xuwu et al. (2016) Insight into the Dual Functions of Bacterial Enhancer-Binding Protein Rrp2 of Borrelia burgdorferi. J Bacteriol 198:1543-52
Radolf, Justin D; Deka, Ranjit K; Anand, Arvind et al. (2016) Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen. Nat Rev Microbiol 14:744-759

Showing the most recent 10 out of 27 publications