The spirochete Borrelia burgdorferi is the causative agent of Lyme disease. Infected mammals produce bacteriocidal antibodies against B. burgdorferi surface proteins, and passive transfer of sera from infected humans and laboratory animals can protect na?ve animals against B. burgdorferi challenge. Yet antibodies directed against B. burgdorferi often cannot effectively clear infection, and bacteria can persistently infect humans and other mammals with periodic recurrence of symptoms. These observations suggest that B. burgdorferi alters its surface properties during mammalian infection to evade clearance by the host immune system. Consistent with this prediction, it is well known that B. burgdorferi can regulate the synthesis of antigenic surface proteins, both in vivo and in vitro. Within the first four weeks of infection, mammals produce antibodies against the B. burgdorferi Erp lipoproteins, indicating that the bacteria synthesize Erp proteins during this time period. It is proposed that Erp proteins are involved in the initial infection process by enabling B. burgdorferi to be transmitted from the tick vector and/or interact with mammalian tissues. Infected mammals consistently produce antibodies directed against Erp proteins, but can still be chronically infected by B. burgdorferi. As a corollary to the central hypothesis, it is predicted that Erp proteins are not produced during the later stages of mammalian infection. B. burgdorferi can regulate the synthesis of Erp proteins in culture, and it is hypothesized that Erp protein production is also regulated by similar mechanisms in vivo.
The specific aims of the proposed studies are: (1) Characterize erp genes and their proteins in cultured bacteria by investigating the in vitro differential expression of erp mRNAs and proteins, the ability of individual bacteria to simultaneously express their entire repertoire of Erp proteins, the surface accessibility of each Erp protein, and the ability of antibodies directed against Erp proteins to inhibit B. burgdorferi growth. (2) Analyze erp genes and their proteins during mammal and tick infections by examining levels of erp transcripts and Erp proteins throughout the mammal-tick infectious cycle. (3) At this time, essentially nothing is known about the regulatory mechanisms that govern expression of the erp genes or any other B. burgdorferi gene. Cultured bacteria will be used to further characterize mechanisms of erp gene regulation, including the continued purification of a B. burgdorferi protein that specifically binds to erp promoter DNA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044254-03
Application #
6511131
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Baker, Phillip J
Project Start
2000-03-01
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
3
Fiscal Year
2002
Total Cost
$289,600
Indirect Cost
Name
University of Kentucky
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Kraiczy, Peter; Stevenson, Brian (2013) Complement regulator-acquiring surface proteins of Borrelia burgdorferi: Structure, function and regulation of gene expression. Ticks Tick Borne Dis 4:26-34
Jutras, Brandon L; Jones, Grant S; Verma, Ashutosh et al. (2013) Posttranscriptional self-regulation by the Lyme disease bacterium's BpuR DNA/RNA-binding protein. J Bacteriol 195:4915-23
Jutras, Brandon L; Chenail, Alicia M; Carroll, Dustin W et al. (2013) Bpur, the Lyme disease spirochete's PUR domain protein: identification as a transcriptional modulator and characterization of nucleic acid interactions. J Biol Chem 288:26220-34
Brisson, Dustin; Zhou, Wei; Jutras, Brandon L et al. (2013) Distribution of cp32 prophages among Lyme disease-causing spirochetes and natural diversity of their lipoprotein-encoding erp loci. Appl Environ Microbiol 79:4115-28
Jutras, Brandon L; Chenail, Alicia M; Stevenson, Brian (2013) Changes in bacterial growth rate govern expression of the Borrelia burgdorferi OspC and Erp infection-associated surface proteins. J Bacteriol 195:757-64
Jutras, Brandon L; Verma, Ashutosh; Stevenson, Brian (2012) Identification of novel DNA-binding proteins using DNA-affinity chromatography/pull down. Curr Protoc Microbiol Chapter 1:Unit1F.1
Chenail, Alicia M; Jutras, Brandon L; Adams, Claire A et al. (2012) Borrelia burgdorferi cp32 BpaB modulates expression of the prophage NucP nuclease and SsbP single-stranded DNA-binding protein. J Bacteriol 194:4570-8
Radolf, Justin D; Caimano, Melissa J; Stevenson, Brian et al. (2012) Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes. Nat Rev Microbiol 10:87-99
Jutras, Brandon L; Verma, Ashutosh; Adams, Claire A et al. (2012) BpaB and EbfC DNA-binding proteins regulate production of the Lyme disease spirochete's infection-associated Erp surface proteins. J Bacteriol 194:778-86
Jutras, Brandon L; Bowman, Amy; Brissette, Catherine A et al. (2012) EbfC (YbaB) is a new type of bacterial nucleoid-associated protein and a global regulator of gene expression in the Lyme disease spirochete. J Bacteriol 194:3395-406

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