Lyme disease is the most commonly reported arthropod-borne infectious disease in the United States and Europe. The causative agent, B. burgdorferi, infects humans as accidental hosts via tick bites. Little is known about the importance of Borrelia components to infection or virulence. Our long-term goal is to elucidate virulence determinants and mechanisms of virulence as a prerequisite to developing therapeutic protocols for treatment of Lyme arthritis and prevention of the disease. The objective of this application is to determine the role of the Shk-Grr putative signaling system in the infectious cycle of B. burgdorferi. By generating the Shk-Grr-deficient mutants in infectious B. burgdorferi strains, our preliminary studies lead to the hypothesis that Shk-Grr is involved in spirochete adaptation in tick vectors. To test this hypothesis, we propose 1), to quantitatively determine the mutants' spirochete loads in various mouse organs as well as in ticks at various time points during feeding. Such studies should pinpoint the exact defect(s) of the mutant during its natural cycle; 2) to globally examine the influence of Shk-Grr-deficiency in gene expression by a microarray approach. Accomplishing the proposed aims will not only have an important impact in our understanding of the infectious cycle of B. burgdorferi, but also improve our understanding of vector- pathogen interaction and bacterial signal transduction in general. ? ? Accomplishing the specific aims outlined in this proposal will likely yield the discovery of a new regulatory pathway that is important for the infectious cycle of the Lyme disease pathogen. This will not only advance our understanding the molecular mechanism of the pathogenesis of Lyme disease, but also will lead to identification of new antimicrobial targets for disrupting the pathogen's transmission cycle. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI072144-01A1
Application #
7314067
Study Section
Special Emphasis Panel (ZRG1-IDM-A (90))
Program Officer
Breen, Joseph J
Project Start
2007-07-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$214,375
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
He, Ming; Ouyang, Zhiming; Troxell, Bryan et al. (2011) Cyclic di-GMP is essential for the survival of the lyme disease spirochete in ticks. PLoS Pathog 7:e1002133
Blevins, Jon S; Xu, Haijun; He, Ming et al. (2009) Rrp2, a sigma54-dependent transcriptional activator of Borrelia burgdorferi, activates rpoS in an enhancer-independent manner. J Bacteriol 191:2902-5
Ouyang, Zhiming; He, Ming; Oman, Tara et al. (2009) A manganese transporter, BB0219 (BmtA), is required for virulence by the Lyme disease spirochete, Borrelia burgdorferi. Proc Natl Acad Sci U S A 106:3449-54
He, Ming; Oman, Tara; Xu, Haijun et al. (2008) Abrogation of ospAB constitutively activates the Rrp2-RpoN-RpoS pathway (sigmaN-sigmaS cascade) in Borrelia burgdorferi. Mol Microbiol 70:1453-64