Lyme arthritis is caused by infection with the tick-borne spirochete Borrelia burgdorferi and in humans is responsible for a number of symptoms involving the heart, joints, central and peripheral nervous system, and skin. A self-limiting, acute arthritis developing one to several months following infection is reported in 60% of patients not treated at the time of the tick bite. Genetic regulation of disease severity is evident in B. burgdorferi-infected mice as C3H mice display severe arthritis while C57BL/6 (B6) mice develop mild to moderate arthritis. Localized induction of Type I IFN has been associated with severe Lyme arthritis development in C3H mice. B. burgdorferi arthritis associated (Bbaa) Quantitative Trait Loci (QTL) on five chromosomes were previously identified, and reciprocal interval specific congenic lines (ISCL) of mice have been generated and tested for penetrant arthritis phenotypes. ISCL encompassing Bbaa2Bbaa3 on chromosome 5 and Bbaa4 on chromosome 11 transferred arthritis phenotypes in both directions. Interval specific recombinant congenic lines (ISRCL) have been generated within Bbaa2Bbaa3 resulting in significantly delimiting the physical boundaries encompassing the relevant loci. Two loci have been identified with enhanced influence on arthritis phenotype;Bbaa2a at 119.18-125.31Mbp and Bbaa2b at 127.40-137.53Mbp. A third region, Bbaa2c at 125.31-127.40Mbp, suppresses phenotypes attributed to Bbaa2b. ISRCL across the Bbaa4 interval on chromosome 11 have also been generated and physical mapping of the relevant locus is anticipated. The exciting finding of increased phenotype in the narrowed ISRCL is a major advance towards the ultimate goal of identifying the allelic genes responsible for the difference in arthritis severity in B6 and C3H mice following infection with B. burgdorferi. Four approaches that incorporate genetics, molecular biology, and biological characterization are proposed for the identification of these genes: 1) high resolution congenic mapping of Bbaa2a, Bbaa2b, and Bbaa4;2) identification of positional candidates by comparative sequence and expression analysis;3) determine the contribution of Type I IFN to arthritis in each ISRCL;and 4) using RNA silencing to assess candidate genes for modulation of B. burgdorferi signaling in macrophages.

Public Health Relevance

Lyme arthritis is a consequence of infection with the tick borne spirochete Borrelia burgdorferi, and the severity of disease is genetically regulated by the host. Identification of the genes that regulate disease severity will provide insight into the mechanism of arthritis development and may be extended to other inflammatory pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043521-20
Application #
8490159
Study Section
Special Emphasis Panel (ZRG1-IDM-S (02))
Program Officer
Mao, Su-Yau
Project Start
1994-09-30
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
20
Fiscal Year
2013
Total Cost
$439,037
Indirect Cost
$104,905
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Lochhead, Robert B; Ma, Ying; Zachary, James F et al. (2014) MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi. PLoS Pathog 10:e1004212
Ma, Ying; Bramwell, Kenneth K C; Lochhead, Robert B et al. (2014) Borrelia burgdorferi arthritis-associated locus Bbaa1 regulates Lyme arthritis and K/B×N serum transfer arthritis through intrinsic control of type I IFN production. J Immunol 193:6050-60
Bramwell, Kenneth K C; Ma, Ying; Weis, John H et al. (2014) Lysosomal *-glucuronidase regulates Lyme and rheumatoid arthritis severity. J Clin Invest 124:311-20
Bramwell, Kenneth K C; Teuscher, Cory; Weis, Janis J (2014) Forward genetic approaches for elucidation of novel regulators of Lyme arthritis severity. Front Cell Infect Microbiol 4:76
Debnath, Irina; Roundy, Kirstin M; Pioli, Peter D et al. (2013) Bone marrow-induced Mef2c deficiency delays B-cell development and alters the expression of key B-cell regulatory proteins. Int Immunol 25:99-115
Pioli, Peter D; Dahlem, Timothy J; Weis, Janis J et al. (2013) Deletion of Snai2 and Snai3 results in impaired physical development compounded by lymphocyte deficiency. PLoS One 8:e69216
Bramwell, Kenneth K C; Ma, Ying; Weis, John H et al. (2012) High-throughput genotyping of advanced congenic lines by high resolution melting analysis for identification of Bbaa2, a QTL controlling Lyme arthritis. Biotechniques 52:183-90
Sonderegger, F Lynn; Ma, Ying; Maylor-Hagan, Heather et al. (2012) Localized production of IL-10 suppresses early inflammatory cell infiltration and subsequent development of IFN-?-mediated Lyme arthritis. J Immunol 188:1381-93
Ma, Ying; Miller, Jennifer C; Crandall, Hillary et al. (2009) Interval-specific congenic lines reveal quantitative trait Loci with penetrant lyme arthritis phenotypes on chromosomes 5, 11, and 12. Infect Immun 77:3302-11
Koening, Curry L; Miller, Jennifer C; Nelson, Jenifer M et al. (2009) Toll-like receptors mediate induction of hepcidin in mice infected with Borrelia burgdorferi. Blood 114:1913-8

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