Lyme disease is caused by infection with the tick borne spirochete Borreliai burgdorferi and is the most common vector borne disease in the United States. Infection is associated with a spectrum of disease symptoms and severity, with up to 60% of infected patients developing arthritis. Differences in arthritis severity are found in inbred mouse strains, with C3H mice displaying severe disease and C57BL/6 (B6) mice developing mild disease. Using a forward genetic approach we have identified quantitative trait loci (QTL) that regulate the response to B. burgdorferi, with six of these QTL regulating the severity of Lyme arthritis (Bbaa's 1,2,3,4,6,12). Development of advanced recombinant congenic lines allowed the positional cloning of beta- Glucuronidase (Gusb) within Bbaa2 on Chr5, as a major regulator of arthritis severity. The C3H allele of Gusb is hypormorphic, resulting in the accumulation of undigested glycosaminoglycans (GAGs) in joint tissue, which appear to function as a second hit leading to the exacerbation of B. burgdorferi triggered arthriti and rheumatoid arthritis. The current application incorporates mechanistic characterization of the genes identified in the regulation of Lyme arthritis. In the first Aim, GAGs will be biosynthetically labeled and characterized by HPLC and Mass Spectrometry from congenic and transgenic mice in order to identify those enriched in inflammatory arthritis. Click-xylosidses wil then be used to prime GAG synthesis, allowing the recovery and assessment of GAGs with inflammatory potential. Characterization of the GAG-profile in mutant mice will allow documentation of the breadth of exoglycosidases that could be involved in Lyme arthritis development. These findings will be translated to patients with Lyme disease, by quantifying several exoglycosidases involved in GAG degradation in samples from patients at different stages of B. burgdorferi infection and from patients displaying different clinical responses to antibiotic treatment. A bioinformatics approach has been initiated to identify modifiers of GUSB function, and in conjunction with advanced recombinants provides convincing evidence for additional genes linked on Chr5 that modify the arthritis effect of Gusb. Further development of advance recombinant congenics and double congenics are proposed, with the goal of identifying interactions that modulate Lyme arthritis severity. The C3H allele of a second QTL, Bbaa1 on Chr4, also displays a strongly penetrant arthritis phenotype. In this case, arthritis is dependent on the production of Type I IFN. Bbaa1 also encodes the Type I IFN gene cluster. Therefore, the hyperactive expression of Type I IFN previously observed in C3H mice is directly regulated by genes within Bbaa1 and possibly inherent to the IFN locus. Experiments are proposed to study the genetic regulation of Type I IFN and the mechanism by which hyper-production of Type I IFN directs the severity of Lyme arthritis. This application capitalizes on ou prior forward genetic studies of Lyme arthritis and should provide novel and broadly applicable insight into inflammatory pathologies.

Public Health Relevance

Lyme Disease is caused by the spirochete Borreliai burgdorferi, and results in arthritis in up to 60% of infected individuals. Using inbred strains of mice we have identified several genetic regions that regulate the severity of disease. The manner in which these genes influence arthritis development in mice and humans will be pursued in this application and could lead to development of novel treatment regimens.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Mao, Su-Yau
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University of Utah
Schools of Medicine
Salt Lake City
United States
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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
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