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Janis Weis

Professor of Pathology

Janis Weis

B.A. University of Kansas

Ph.D. University of Minnesota Medical School

Research

References

janis.weis@path.utah.edu

Janis Weis' Lab Page

Janis Weis' PubMed Literature Search

Molecular Biology Program

Genetic Regulation of Lyme Disease

Research

My laboratory studies the pathogenesis of Lyme disease; an infection caused by the tick borne spirochete Borrelia burgdorferi.  This is the most common vector borne disease in the United States, responsible for up to 300,000 infections per year in endemic regions.  A spectrum of symptoms and severity are observed in patients, with both bacterial and host factors contributing to the variability.  Our mechanistic studies have focused on characterization of host factors that determine the severity of Lyme disease development, particularly the regulation of arthritis severity in inbred strains of mice.  We have taken two complementary approaches to understanding disease development:  empirical assessment of host responses associated with mild and severe disease, and forward genetics identification of quantitative trait loci (QTL) that regulate disease severity.   These approaches have identified several regulators of Lyme arthritis severity.  We made the surprising observation of a pre-clinical spike in Type I IFN in the joint tissue of C3H mice, several weeks prior to the development of acute Lyme arthritis in this mouse, that was absent from arthritis resistant C57BL/6 mouse. Treatment with IFN receptor blocking antibody or ablation of the IFN receptor gene suppressed arthritis, indicating it required receptor dependent amplification.  A second arthritis model that relies on dysregulated innate host responses has also been identified in collaboration with Ryan O’Connell’s lab:  the miR146a deficient mouse.  Previous studies had implicated the signaling adapter MyD88 and the NF-kB dependent transcriptional response in control of B. burgdorferi infection.  miR-146a is a small RNA that modulates the magnitude of this signaling pathway, and deficiency in miR146a resulted in increased inflammatory responses, without impairing anti-bacterial defenses, thus revealing the contribution of NF-kB signaling in arthritis development.  The IL-10 deficient mouse has provided a third model of severe Lyme arthritis, which mimicked many features of patients with chronic Lyme disease:  failure to resolve inflammation even when bacteria had been cleared from joint tissue.  Both disease promoting IFNγ and disease suppressing IL-10 were produced by B. burgdorferi specific T lymphocytes, rendering this a model to study T cell responses in chronic inflammation.

In our forward genetics approach we have identified 23 QTL that regulate the response to B. burgdorferi infection, with 6 regulating arthritis severity and several displaying penetrant arthritis phenotypes in congenic mice.  Development of advanced congenic mice with single polymorphic genetic difference allowed the positional cloning of beta-glucuronidase (Gusb) as a major regulator of Lyme arthritis severity.  The C3H allele was associated with accumulation of pro-arthritic glyclosaminoglycans in the joint tissue of infected mice.  Importantly, the Gusb polymorphism also regulates the severity of an autoimmune rheumatoid arthritis model.  Current studies are focused on translational analysis of Gusb and related lysosomal components in Lyme and rheumatoid arthritis patients, and determining if modulating the expression of Gusb can influence these arthritis phenotypes.  These studies predict a new paradigm in risk factors for arthritis development and could lead to novel treatments for Lyme and rheumatoid arthritis patients.

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References

  1. Paquette JK*, Ma Y*, Fisher C, Li J*, Lee SB, Zachary JF‡, Kim YS†, Teuscher C§, Weis JJ*. Lyme arthritis regulated by the Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1) is dependent on localized production of IFN beta and requires up regulation of myostatin.  In press, Journal of Immunology
  2. Bramwell KK, Mock K, Ma Y, Weis JH, Teuscher C, Weis JJ. β-Glucuronidase, a Regulator of Lyme Arthritis Severity, Modulates Lysosomal Trafficking and MMP-9 Secretion in Response to Inflammatory Stimuli. 2015. J Immunol 195:1647-56.
  3. Lochhead RB, Zachary JF, Dalla Rosa L, Ma Y, Weis JH, O'Connell RM, Weis JJ. Antagonistic Interplay between MicroRNA-155 and IL-10 during Lyme Carditis and Arthritis. 2015. PLoS One 10:e0135142. PMCID: PMC4529177
  4. Ma Y, Bramwell KK, Lochhead RB, Paquette JK, Zachary JF, Weis JH, Teuscher C, Weis JJ. Borrelia burgdorferi arthritis-associated locus Bbaa1 regulates Lyme arthritis and K/B×N serum transfer arthritis through intrinsic control of type I IFN production. 2014. J Immunol 193:6050-60. PMCID: PMC4258437
  5. Lochhead RB, Ma Y, Zachary JF, Baltimore D, Zhao JL, Weis JH, O'Connell RM, Weis JJ. MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi. 2014. PLoS Pathog 10:e1004212. PMCID: PMC4072785
  6. Bramwell KK, Teuscher C, Weis JJ. Forward Genetics approaches for elucidation of novel regulators of Lyme arthritis severity. 2014. Front Cell Infect Microbiol 4:76. PMCID:PMC4046100
  7. Bramwell KK, Ma Y, Weis JH, Chen X, Zachary JF, Teuscher C, Weis JJ. Lysosomal β-glucuronidase regulates Lyme and rheumatoid arthritis severity. 2014. J Clin Invest 124:311-320. PMCID:PMC3871255
  8. Lochhead RB*, Sonderegger FL*, Ma Y*, Brewster JE, Cornwall D, Maylor-Hagan H, Miller JC, Zachary JF, Weis JH, Weis JJ. Endothelial cells and fibroblasts amplify the arthritogenic Type I IFN response in murine Lyme disease and are major sources of chemokines in B. burgdorferi-infected joint tissue. 2012. J Immunol 189:2488-2501. PMCID:PMC3424307
  9. Sonderegger FL, Ma Y, Maylor-Hagan H, Brewster J, Huang X, Spangrude GJ, Zachary JF, Weis JH, Weis JJ. Localized Production of IL-10 Suppresses Early Inflammatory Cell Infiltration and Subsequent Development of IFN-g-Mediated Lyme Arthritis. 2012. J Immunol 188:1381-1393. PMCID:PMC3262892
  10. Miller JC, Maylor-Hagen H, Ma Y, Weis JH, Weis JJ. The Lyme disease spirochete Borrelia burgdorferi utilizes multiple ligands, including RNA, for IRF3-dependent induction of Type I IFN-responsive genes. 2010. Infect and Immun 78:3144-3153. PMCID:PMC2897372
  11. Ma Y, Miller JC, Crandall H, Larsen E, Dunn DM, Weiss RB, Subramanian M, Weis JH, Zachary J, Teuscher C, Weis JJ. Interval-specific congenic lines reveal QTL with penetrant Lyme arthritis phenotypes on chromosomes 5, 11, and 12. 2009. Infect Immun 77:3302-3311. PMCID:PMC2715682
  12. Miller JC, Ma Y, Bian J, Sheehan KCF, Zachary JF, Weis JH, Schreiber RD, Weis JJ. Critical role for Type I IFN in arthritis development following Borrelia burgdorferi infection of mice. 2008. J Immunol 181:8492-8503. PCMID:PMC3024833

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Last Updated: 8/21/17