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Infection and Immunity, August 2009, p. 3302-3311, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.00396-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Interval-Specific Congenic Lines Reveal Quantitative Trait Loci with Penetrant Lyme Arthritis Phenotypes on Chromosomes 5, 11, and 12{triangledown}

Ying Ma,1 Jennifer C. Miller,1 Hillary Crandall,1 Eric T. Larsen,1 Diane M. Dunn,2 Robert B. Weiss,2 Meenakumari Subramanian,3 John H. Weis,1 James F. Zachary,4 Cory Teuscher,3 and Janis J. Weis1*

Department of Pathology,1 Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112,2 Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802,3 Departments of Medicine and Pathology, University of Vermont, Burlington, Vermont 054054

Received 8 April 2009/ Returned for modification 9 May 2009/ Accepted 24 May 2009

The observation that Borrelia burgdorferi-induced arthritis is severe in C3H mice and milder in C57BL/6 (B6) mice has allowed a forward genetics approach for the identification of genetic elements that regulate the arthritis response. Quantitative trait loci (QTL) on five chromosomes (Chr) were identified previously in segregating crosses between C3H and B6 mice and collectively designated B. burgdorferi arthritis-associated (Bbaa) QTL. Reciprocal interval-specific congenic lines (ISCL) that encompass Bbaa1, Bbaa2-Bbaa3, Bbaa4, Bbaa6, and Bbaa12 on Chr 4, 5, 11, 12, and 1, respectively, have now been generated. Bidirectional transfer of the arthritis severity phenotype in association with Bbaa2-Bbaa3 and Bbaa4 was observed, and unidirectional transfer with the B6 allele of Bbaa6 was noted. These findings confirm the existence of polymorphic loci within Bbaa2-Bbaa3, Bbaa4, and Bbaa6 that regulate the severity of B. burgdorferi-induced arthritis. ISCL were used to assess the regulation of a previously identified interferon transcriptional profile associated with severe disease in C3H mice. The regulation of this transcriptional signature was found to be independent of penetrant Bbaa QTL, both in joint tissues and in isolated macrophages. These results clearly demonstrate the utility of forward genetics for the discovery of novel genes and pathways involved in the regulation of the severity of Lyme arthritis and predict the involvement of regulatory elements not evident from other experimental approaches.

* Corresponding author. Mailing address: 15 North Medical Dr. East #2100, Salt Lake City, UT 84112-5650. Phone: (801) 581-8386. Fax: (801) 581-4517. E-mail: janis.weis{at}path.utah.edu

{triangledown} Published ahead of print on 1 June 2009.

Editor: A. J. Bäumler

Infection and Immunity, August 2009, p. 3302-3311, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.00396-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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