Antigenic variation plays a vital role in the pathogenesis of many infectious agents, most notably bacteria and protozoa that cause chronic infections. Borrelia burgdorferi and related organisms cause Lyme disease, a multistage, systemic infection that is transmitted by Ixodes ticks and has dermatologic, neurologic, arthralgic, and constitutional manifestations in humans and other animals. B. burgdorferi and other Lyme disease borrelia have an elaborate antigenic variation system consisting of vlsE, a gene expressing a surface-exposed lipoprotein, and a series of vls silent cassettes, which serve as the source of sequences for random, segmental gene conversion events that change the sequence of the central cassette region of vlsE. Although the occurrence of sequence and antigenic variation has been established, little is known about the biological importance of the vls system. In this project, several approaches will be used to address this question.
In Specific Aim 1, vlsE gene disruption and complementation with a shuttle vector containing vlsE and silent cassettes will be utilized to determine whether the vls system is required for mammalian infection. To better understand the requirements for the regulation of vlsE sequence variation and gene expression, reporter constructs, recombinant vls systems, and mutational analysis will be utilized to examine the the roles of cis-acting DNA elements in these processes (Specific Aim 2). Finally, the effects of sequence variation and genetic heterogeneity among different strains on the unique structure of VlsE will be determined in Specific Aim 3. These results will be used to assess the role of VlsE in immunoprotection and immune evasion and in possible functional roles, including host cell and extracellular matrix interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037277-18
Application #
7596461
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Breen, Joseph J
Project Start
1994-09-01
Project End
2010-09-12
Budget Start
2009-04-01
Budget End
2010-09-12
Support Year
18
Fiscal Year
2009
Total Cost
$345,323
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Pathology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Edmondson, Diane G; Prabhakaran, Sabitha; Norris, Steven J et al. (2017) Enhanced Protective Immunogenicity of Homodimeric Borrelia burgdorferi Outer Surface Protein C. Clin Vaccine Immunol 24:
Norris, Steven J (2014) vls Antigenic Variation Systems of Lyme Disease Borrelia: Eluding Host Immunity through both Random, Segmental Gene Conversion and Framework Heterogeneity. Microbiol Spectr 2:
Magnarelli, Louis A; Williams, Scott C; Norris, Steven J et al. (2013) Serum antibodies to Borrelia burgdorferi, Anaplasma phagocytophilum, and Babesia microti in recaptured white-footed mice. J Wildl Dis 49:294-302
Magnarelli, Louis A; Norris, Steven J; Fikrig, Erol (2012) Serum antibodies to whole-cell and recombinant antigens of Borrelia burgdorferi in cottontail rabbits. J Wildl Dis 48:12-20
Norris, Steven J (2012) How do lyme borrelia organisms cause disease? The quest for virulence determinants(). Open Neurol J 6:119-23
Norris, Steven J; Howell, Jerrilyn K; Odeh, Evelyn A et al. (2011) High-throughput plasmid content analysis of Borrelia burgdorferi B31 by using Luminex multiplex technology. Appl Environ Microbiol 77:1483-92
Coutte, Loïc; Botkin, Douglas J; Gao, Lihui et al. (2009) Detailed analysis of sequence changes occurring during vlsE antigenic variation in the mouse model of Borrelia burgdorferi infection. PLoS Pathog 5:e1000293
Lin, Tao; Gao, Lihui; Edmondson, Diane G et al. (2009) Central role of the Holliday junction helicase RuvAB in vlsE recombination and infectivity of Borrelia burgdorferi. PLoS Pathog 5:e1000679
Embers, Monica E; Liang, Fang Ting; Howell, Jerrilyn K et al. (2007) Antigenicity and recombination of VlsE, the antigenic variation protein of Borrelia burgdorferi, in rabbits, a host putatively resistant to long-term infection with this spirochete. FEMS Immunol Med Microbiol 50:421-9
Norris, Steven J (2006) Antigenic variation with a twist--the Borrelia story. Mol Microbiol 60:1319-22

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