: NOTE: The primary modification to the abstract below is that the sentence indicating that we will have to develop a genetic manipulation sysfrytem has been deleted. This has been accomplished and as a result that language has been re-phrased to reflect this. ,r- -4- -C) Other aspects of the abstract did not require revision f13 The Borrelia are causative agents of important human diseases including Lyme disease and relapsing fever. In N. America, Lyme disease is caused by B. burgdorferi, B. garinhi, and B. afzelii and relapsing fever is caused by Borrelia hermsii and B. turicatae. Both infections are multi-systemic disorders with potentially serious clinical outcomes. Lyme disease is a significant problem in endemic regions of the United States and Europe with over 75,000 cases per year. Several recent outbreaks of relapsing fever have occurred in N. America and Europe and the disease remains a continuous problem in Africa. A key pathogenic feature of the Borrelia is their ability to evade early immune-mediated destruction and persist in mammals. Several y++ v-. E>L'cm gin' can 3;M .gym vii complement and opsonophagocytosis is through the binding of members of the factor H (FH) cell adhesion and cell spreading. These proteins are abundant in serum, interstitial fluids, and family of complement regulatory proteins. The host produced-FH proteins normally function as contributing mechanisms have been identified. One means by which the Borrelia circumvent negative regulators of the alternative complement cascade and play an important role in host -.r- U)> C.- adherence and tissue invasion. The contributions of the FH-pathogen interaction in urine and are found in association with platelets, blood cells, anchorage dependent cells basis of the FH/FHL-1-microbe interaction, further characterize a newly defined interaction pathogenesis are now firmly established.
The aims of this proposal are to define the molecular means to down-regulate complement at the cell surface and as a means of facilitating (endotheliurn, epithelium) and the extracellular matrix (ECM). Pathogens exploit FH binding as a -Op 5== CAD U-0 between Borrelia FH binding proteins and additional serum proteins including plasminogen and with a wide range of human pathogens. obtained in understanding the molecular basis, and biological role of the FH/FHL-1 interaction the Borrelia. The broader significance of this proposal lies in the applicability of the information our understanding of the molecular pathogenesis, persistence and adherence mechanisms of relapsing fever spirochetes as a model. In summary, the analyses proposed here will enhance utilize genetic manipulation to dissect the contributions of these virulence mechanisms using the ''- ??'""""""""0_ an' N-0 n""""""""30-om3.o -O= (it

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037787-12
Application #
7843508
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Breen, Joseph J
Project Start
1996-06-15
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
12
Fiscal Year
2010
Total Cost
$355,435
Indirect Cost
Name
Virginia Commonwealth University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Kostick, Jessica L; Szkotnicki, Lee T; Rogers, Elizabeth A et al. (2011) The diguanylate cyclase, Rrp1, regulates critical steps in the enzootic cycle of the Lyme disease spirochetes. Mol Microbiol 81:219-31
Marconi, Richard T; McDowell, John V (2011) Tick salivary proteins offer the lyme disease spirochetes an easy ride and another way to hide. Cell Host Microbe 10:95-6
Freedman, John C; Rogers, Elizabeth A; Kostick, Jessica L et al. (2010) Identification and molecular characterization of a cyclic-di-GMP effector protein, PlzA (BB0733): additional evidence for the existence of a functional cyclic-di-GMP regulatory network in the Lyme disease spirochete, Borrelia burgdorferi. FEMS Immunol Med Microbiol 58:285-94
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McDowell, John V; Wolfgang, Jill; Tran, Emily et al. (2003) Comprehensive analysis of the factor h binding capabilities of borrelia species associated with lyme disease: delineation of two distinct classes of factor h binding proteins. Infect Immun 71:3597-602
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