Lyme disease is a significant threat to human health throughout many parts of the USA. The causative agent, Borrelia burgdorferi, is maintained in nature by infectious cycles involving ticks and many species of vertebrates, with humans being incidental hosts. Understanding the mechanisms by which B. burgdorferi infects humans and is transmitted from vector ticks will be important in development of improved methodologies to prevent and treat this disease. During transmission from tick to mammal, 6. burgdorferi significantly increases expression levels of the Erp family of outer surface proteins. Expression of Erp proteins decreases dramatically during colonization of vector ticks. All natural isolates of B. burgdorferi encode multiple Erp lipoproteins, a ubiquity that is highly suggestive of important roles for these proteins in B. burgdorferi biology. Many Erp proteins have been demonstrated to bind the human complement regulator factor H in vitro, raising the possibility that these proteins may function in vivo to protect the bacteria from killing by the host's innate immune system. Based on results of our previous studies, we hypothesize that Erp proteins perform functions that are absolutely critical to B. burgdorferi infectious processes, and that these functions necessitate the bacteria regulate Erp expression. To test this hypothesiswe will (1) define the roles of Erp proteins in pathogenesis through analyses of specific B. burgdorferi erp mutants for their abilities to bind factor H, resist complement-mediated killing, and infect mice and ticks;(2) examine mechanisms by which B. burgdorferi controls Erp expression, including innovative analyses of transcription throughout mammalian and tick infection;and (3) characterize functions of the novelDMA binding proteins we discovered that specifically bind to erp operator DMA. Results of our studies will provide important insight into the mechanisms by which B. burgdorferi infects humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044254-10
Application #
7782689
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Breen, Joseph J
Project Start
2000-03-01
Project End
2013-02-28
Budget Start
2010-03-01
Budget End
2013-02-28
Support Year
10
Fiscal Year
2010
Total Cost
$345,384
Indirect Cost
Name
University of Kentucky
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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
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; 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
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
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; 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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