Infection with Borrelia burgdorferi leads to Lyme disease, which is the leading arthropod-borne infectious agent in the United States. Despite the prevalence of this disease, little is understood about the molecular pathogenesis of this infection. Inasmuch as bacterial adherence to host tissues is recognized as a critical component of the pathogenic process, we therefore propose to further characterize the B. burgdorferi decorin binding and BBK32 adhesins that bind to host decorin and fibronectin, respectively. Characterization of the adhesive properties of these borrelial microbial surface components that recognize extracellular matrix molecules will be conducted in concert with studies to address the infectivity of strains whose adhesin genes have been genetically inactivated either individually or in combination. To further characterize the borrelial lipoprotein adhesins and their respective mutants, we propose the following Specific Aims: (1) Define the role of the fibronectin binding BBK32 in B. burgdorferi pathogenesis;(2) Further characterize the role of the decorin binding proteins in B. burgdorferi pathogenesis;and (3) Evaluate the importance of selected lipoproteins in the molecular pathogenesis of B. burgdorferi infections. We have genetically inactivated the fibronectin binding adhesin in an infectious isolate of B. burgdorferi and have strong preliminary evidence that fibronectin binding participates in secondary colonization and/or protects the organism against clearance. This mutant represents the first genetic knockout in a lipoprotein encoding loci that has a known adhesive activity that targets a mammalian ligand. Similar analyses are planned for the genes encoding the decorin binding protein adhesins as well as genetic studies to evaluate a panel of novel lipoproteins for their importance for borrelial pathogenesis. Following initial characterization studies using in vitro correlates of infection, i.e., adhesion and invasion, we will then determine the molecular mechanism(s) these adhesins use to colonize, disseminate, and/or persist within the infected mammalian host(s).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058086-05
Application #
7774393
Study Section
Special Emphasis Panel (ZRG1-HIBP (09))
Program Officer
Breen, Joseph J
Project Start
2006-03-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$343,026
Indirect Cost
Name
Texas A&M University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Ebady, Rhodaba; Niddam, Alexandra F; Boczula, Anna E et al. (2016) Biomechanics of Borrelia burgdorferi Vascular Interactions. Cell Rep 16:2593-2604
Garcia, Brandon L; Zhi, Hui; Wager, Beau et al. (2016) Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex. PLoS Pathog 12:e1005404
Zhi, Hui; Weening, Eric H; Barbu, Elena Magda et al. (2015) The BBA33 lipoprotein binds collagen and impacts Borrelia burgdorferi pathogenesis. Mol Microbiol 96:68-83
Moriarty, Tara J; Shi, Meiqing; Lin, Yi-Pin et al. (2012) Vascular binding of a pathogen under shear force through mechanistically distinct sequential interactions with host macromolecules. Mol Microbiol 86:1116-31
Hyde, Jenny A; Weening, Eric H; Skare, Jon T (2011) Genetic transformation of Borrelia burgdorferi. Curr Protoc Microbiol Chapter 12:Unit 12C.4
Wu, Jing; Weening, Eric H; Faske, Jennifer B et al. (2011) Invasion of eukaryotic cells by Borrelia burgdorferi requires ýý(1) integrins and Src kinase activity. Infect Immun 79:1338-48
Hyde, Jenny A; Weening, Eric H; Chang, Mihee et al. (2011) Bioluminescent imaging of Borrelia burgdorferi in vivo demonstrates that the fibronectin-binding protein BBK32 is required for optimal infectivity. Mol Microbiol 82:99-113
Prabhakaran, Sabitha; Liang, Xiaowen; Skare, Jonathan T et al. (2009) A novel fibronectin binding motif in MSCRAMMs targets F3 modules. PLoS One 4:e5412
Weening, Eric H; Parveen, Nikhat; Trzeciakowski, Jerome P et al. (2008) Borrelia burgdorferi lacking DbpBA exhibits an early survival defect during experimental infection. Infect Immun 76:5694-705