Janis J. Weis, PhD
- Microbial Pathogenesis
- Genetic Regulation of Lyme Disease Severity
- Pathogenesis of Borrelia Burgdorferi
- Departments: Pathology - Professor
- Divisions: Microbiology and Immunology
Academic Office Information
Emma Eccles Jones Research Building
15 North Medical Drive East, Room: 1720B
Salt Lake City, UT 84112
Research StatementThe research in my laboratory is focused on understanding the means by which microbial infections result in acute and chronic inflammatory pathologies. We use the murine model of Lyme disease to assess the development of arthritis following infection by the spirochete Borrelia burgdorferi. We are taking two complementary approaches to identifying host responses that both permit chronic infection and result in arthritis. The first approach has centered on identifying the tissue-specific response to B. burgdorferi and its products that results in arthritis development. Comparison of responses in mouse strains destined to develop severe disease has revealed an exaggerated induction of interferon-inducible genes. In C3H mice this response is due to Type I IFN, is transient, and is clearly correlated with the subsequent infiltration of myeloid cells character¬istic of this arthritis. The ensuing synovial hyperproliferation in the infected tissue is also characteristic of human disease. Type I IFN is strongly associated with other inflammatory pathologies including Lupus and has been found in a subset of patients with Rheumatoid Arthritis. Intriguingly, this response is absent from mouse strains displaying mild arthritis, and the differential response can be studied in relevant cells from the joint tissue. Current analysis involves genetic and epigenetic regulation of the IFN locus, and the possible involvement of microRNAs in this response. A second model for chronic Lyme arthritis involves mice lacking the non-redundant inflammatory cytokine IL-10. In the absence of IL-10, arthritis is driven by a classic T cell dependent Type II IFN response to localized bacteria. Analysis of tissue infiltrate into the joint and use of cytokine reporter mice have revealed inflammatory cells responsible for arthritis regulation and for the development of arthritis in dysregulated situations. This model has many similarities to patients with chronic Lyme Disease.
We also utilize the mouse for the identi¬fication of the genetic elements that regulate the severity of Lyme arthritis. Epidemiological studies in humans support the existence of polymor¬phic genes that determine the severity of disease, and indicate that alleles of these genes may also set the stage for chronic conditions potentially involving autoimmune pathways. Intercross populations between mildly and severely arthritic strains of mice revealed multiple genetic loci (Quantitative Trait Loci or QTL) on five chromosomes of the mouse that regulate the severity of disease. The development of Interval Specific Congenic Lines of mice has allowed isolation of these loci and demonstration of associated penetrant arthritis phenotypes. Further delineation of the regions of interest through the development of recombinant congenics has led to the characterization of multiple sub-loci and reduced the associated intervals to 1-2Mbp. We are currently are poised to isolate invidual loci on unique recombinant congenic mouse lines and assessment of contribution to arthritis severity. Analysis of available SNP databases has allowed selection of several candidate genes. These are currently being assessed for effect on arthritis severity by a combination of cell biology experi¬mentation and by the development of allele-specific transgenic mice.
|Postdoctoral Fellowship||Harvard Medical School and Brigham and Women's Hospital
Medicine and Rheumatology & Immunology
|Doctoral Training||University of Minnesota
|Undergraduate||University of Kansas
- Lochhead RB, Ma Y, Zachary JF, Baltimore D, Zhao JL, Weis JH, OConnell RM, Weis JJ (2014). MicroRNA-146a Provides Feedback Regulation of Lyme Arthritis but Not Carditis during Infection with Borrelia burgdorferi. PLoS Pathog, 10(6), e1004212.
- Bramwell KK, Ma Y, Weis JH, Chen X, Zachary JF, Teuscher C, Weis JJ (2014). Lysosomal beta-glucuronidase regulates Lyme and rheumatoid arthritis severity. J Clin Invest, 124(1), 311-20.
- Lochhead RB, Sonderegger FL, Ma Y, Brewster JE, Cornwall D, Maylor-Hagen H, Miller JC, Zachary JF, Weis JH, Weis JJ (2012). Endothelial cells and fibroblasts amplify the arthritogenic type I IFN response in murine Lyme disease and are major sources of chemokines in Borrelia burgdorferi-infected joint tissue. J Immunol, 189(5), 2488-501.
- Bramwell KK, Ma Y, Weis JH, Teuscher C, Weis JJ (2012). High-throughput genotyping of advanced congenic lines by high resolution melting analysis for identification of Bbaa2, a QTL controlling Lyme arthritis. Biotechniques, 52(3), 183-90.
- Sonderegger FL, Ma Y, Maylor-Hagan H, Brewster J, Huang X, Spangrude GJ, Zachary JF, Weis JH, Weis JJ (2012). Localized production of IL-10 suppresses early inflammatory cell infiltration and subsequent development of IFN-gamma-mediated Lyme arthritis. J Immunol, 188(3), 1381-93.
- Miller JC, Maylor-Hagen H, Ma Y, Weis JH, Weis JJ (2010). The Lyme disease spirochete Borrelia burgdorferi utilizes multiple ligands, including RNA, for interferon regulatory factor 3-dependent induction of type I interferon-responsive genes. Infect Immun, 78(7), 3144-53.
- Ma Y, Miller JC, Crandall H, Larsen ET, Dunn DM, Weiss RB, Subramanian M, Weis JH, Zachary JF, Teuscher C, Weis JJ (2009). Interval-specific congenic lines reveal quantitative trait Loci with penetrant lyme arthritis phenotypes on chromosomes 5, 11, and 12. Infect Immun, 77(8), 3302-11.
- Miller JC, Ma Y, Bian J, Sheehan KC, Zachary JF, Weis JH, Schreiber RD, Weis JJ (2008). A critical role for type I IFN in arthritis development following Borrelia burgdorferi infection of mice. J Immunol, 181(12), 8492-503.
- Wang X, Ma Y, Yoder A, Crandall H, Zachary JF, Fujinami RS, Weis JH, Weis JJ (2008). T cell infiltration is associated with increased Lyme arthritis in TLR2-/- mice. FEMS Immunol Med Microbiol, 52(1), 124-33.
- Rogers SW, Weis JJ, Ma Y, Teuscher C, Gahring LC (2008). Mouse chromosome 11 harbors genetic determinants of hippocampal strain-specific nicotinic receptor expression. Hippocampus, 18(8), 750-7.
- Stewart, PE, Wang, X, Bueschel DM, Clifton DR, Grimm, D, Tilly, K, Carroll JA, Weis JJ, Rosa PA (2006). Delineating the requirement for the Borrelia burgdorferi virulence factor OspC in the mammalian host. Infect Immun, (74), 3547-3553.
- Crandall H, Ma Y, Dunn DM, Sundsbak RS, Zachary JF, Olofsson P, Holmdahl R, Weis JH, Weiss RB, Teuscher C, Weis JJ (2005). Bb2Bb3 Regulation of Murine Lyme Arthritis Is Distinct from Ncf1 and Independent of the Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase. Am J Pathol, 167(3), 775-85.
- Wang X, Ma Y, Weis JH, Zachary JF, Kirschning CJ, Weis JJ (2005). Relative contributions of innate and acquired host responses to bacterial control and arthritis development in Lyme disease. Infect Immun, 73(1), 657-60.
- Bolz DD, Sundsbak RS, Ma Y, Akira S, Kirschning CJ, Zachary JF, Weis JH, Weis JJ (2004). MyD88 plays a unique role in host defense but not arthritis development in Lyme disease. J Immunol, 173(3), 2003-10.
- Wooten RM, Ma Y, Yoder RA, Brown JP, Weis JH, Zachary JF, Kirschning CJ, Weis JJ (2002). Toll-like receptor 2 is required for innate, but not acquired, host defense to Borrelia burgdorferi. J Immunol, 168(1), 348-55.
- Roper RJ, Weis JJ, McCracken BA, Green CB, Ma Y, Weber KS, Fairbairn D, Butterfield RJ, Potter MR, Zachary JF, Doerge RW, Teuscher C (2001). Genetic control of susceptibility to experimental Lyme arthritis is polygenic and exhibits consistent linkage to multiple loci on chromosome 5 in four independent mouse crosses. Genes Immun, 2(7), 388-97.
- Hirschfeld M, Weis JJ, Toshchakov V, Salkowski CA, Cody MJ, Ward DC, Qureshi N, Michalek SM, Vogel SN (2001). Signaling by toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages. Infect Immun, 69(3), 1477-82.
- Hirschfeld M, Ma Y, Weis JH, Vogel SN, Weis JJ (2000). Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J Immunol, 165(2), 618-22.
- Brown JP, Zachary JF, Teuscher C, Weis JJ, Wooten RM (1999). Dual role of interleukin-10 in murine Lyme disease: regulation of arthritis severity and host defense. Infect Immun, 67(10), 5142-50.
- Hirschfeld M, Kirschning CJ, Schwandner R, Wesche H, Weis JH, Wooten RM, Weis JJ (1999). Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2. J Immunol, 163(5), 2382-6.
- Morrison TB, Ma Y, Weis JH, Weis JJ (1999). Rapid and sensitive quantification of Borrelia burgdorferi-infected mouse tissues by continuous fluorescent monitoring of PCR. J Clin Microbiol, 37(4), 987-92.
- Weis JJ, McCracken BA, Ma Y, Fairbairn D, Roper RJ, Morrison TB, Weis JH, Zachary JF, Doerge RW, Teuscher C (1999). Identification of quantitative trait loci governing arthritis severity and humoral responses in the murine model of Lyme disease. J Immunol, 162(2), 948-56.
- Bramwell KK, Teuscher C, Weis JJ (2014). Forward genetic approaches for elucidation of novel regulators of Lyme arthritis severity. [Review]. Front Cell Infect Microbiol, 4, 76.
- Miller JC, Ma Y, Crandall H, Wang X, Weis JJ (2008). Gene expression profiling provides insights into the pathways involved in inflammatory arthritis development: murine model of Lyme disease. [Review]. Exp Mol Pathol, 85(1), 20-7.
- Bolz DD, Weis JJ (2004). Molecular mimicry to Borrelia burgdorferi: pathway to autoimmunity? [Review]. Autoimmunity, 37(5), 387-92.