Professor of Microbiology and Immunology
B.A. University of Kansas
Ph.D. University of Minnesota Medical School
Janis Weis' Lab Page
Janis Weis' PubMed Literature Search
Molecular Biology Program
Genetic Regulation of Lyme Disease
We study 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. C3H mice develop severe arthritis when infected with B. burgdorferi while arthritis in C57BL/6 mice is mild. Using forward genetics we have identified numerous quantitative trait loci (QTL) that regulate the severity of Lyme arthritis. One of these identified the beta-glucuronidase gene (Gusb) as a major regulator of Lyme arthritis severity, with the defective allele resulting in accumulation of pro-arthritic glyclosaminoglycans in the joint tissue of infected mice. The Gusb polymorphism also regulates the severity of an autoimmune rheumatoid arthritis model. Current studies are focused on 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.
A second QTL, Bbaa1, includes the Type I IFN cluster on mouse Chr4, and regulates arthritis severity through the upregulation of Type I IFN. Development of congenic mouse lines in which the C3H allele of Bbaa1 was introgressed onto the B6 background (B6.C3-Bbaa1) allowed identification of downstream mediators of Lyme arthritis. Surprisingly, the skeletal muscle regulatory protein myostatin, MSTN, was identified as the Type I IFN induced link between B. burgdorferi infection and severe arthritis in B6.C3-Bbaa1 congenic mice. Administration of the inhibitory propeptide of MSTN suppressed the development of Lyme arthritis in these congenic mice. These studies are being pursued in patients with Lyme disease, and in mice with established Lyme arthritis, to determine if upregulation of MSTN is a common feature of Lyme disease and if it could be a potential therapeutic target for patients with persistent arthritis.
We have recently developed a model for one of the most troubling aspects of Lyme disease, the persistence of symptoms after what should have been an effective antibiotic regimen: post treatment Lyme disease (PTLD). We have discovered that arthritis is sustained by bystander activation of CD4+ and CD8+ T lymphocytes. These T cells become a source of arthritis promoting IFNg, leading to inflammatory markers with striking similarity to those seen PTLD patients. B. burgdorferi has long been recognized as a potent stimulant of TLR2 on innate cells. We discovered that CD4 and CD8 bystander T cells have intrinsically upregulated TLR2, and that this is central to their activation and promotion of arthritis. We are working to characterize bystander-activated T cells through single cell expression profiling, with the goal of identifying markers unique to bystander-activated T cells as potential targets for resolution of arthritis.
Two additional Lyme arthritis models that exploit a dysregulated innate host response have been identified in collaboration with Ryan O’Connell’s lab: the miR146a-/- mouse and the miR-155-/- mouse. Previous studies had revealed the central role of the TLR2 adapter MyD88 and the NF-kB dependent transcriptional response in control of B. burgdorferi infection. Studies with miR146a-/- and miR-155-/- mice demonstrate that NF-kB dependent cytokines are also critical for the inflammatory responses leading to arthritis and carditis. These mice will provide models for testing novel therapeutics that reduce inflammation without impairing host defense.
On the cover: Borrelia burgdorferi–infected mice expressing a single TCR transgene for a non–Borrelia epitope develop severe Lyme arthritis, revealing bystander activation of T cells is sufficient to promote disease. Histopathological analysis of joint tissue reveals reactive and thickened synovium covering the tendon sheath, with evident inflammatory infiltrate. Whiteside, S. K., et al., 2018, J. Immunol. 200: 1457–1470.
- Whiteside, SK, Snook JP, Williams MA, Weis JJ. Bystander T cells: A balancing act of friends and foes. 2018, Trends in Immunology. 39:1021-1035.
Whiteside SK, Snook, JP, Ma Y, Sonderegger FL, Fisher C, Petersen, C, Zachary JF, Round JL, Williams MA, Weis JJ. IL-10 deficiency reveals a role for TLR2-dependent bystander activation of T cells in Lyme arthritis. 2018. J Immunology. 200:1457-1470 PMCID:PMC5809275
Paquette JK, Ma Y, Fisher C, Li J, Lee SB, Zachary JF, Kim YS, Teuscher C, Weis JJ. Genetic Control of Lyme Arthritis by Borrelia burgdorferi Arthritis-Associated Locus 1 Is Dependent on Localized Differential Production of IFN-β and Requires Upregulation of Myostatin. 2017. J Immunology. 199:3525-3534. PCMID: PMC5679706
Bramwell KK, Mock K, Ma Y, Weis JH, Zachary JF, Teuscher C, Weis JJ. beta-glucuronidase, a regulator of Lyme arthritis severity, modulates lysosomal trafficking and MMP-9 secretion in response to inflammatory stimuli. 2015. J Immunology 195:1647-56. PMCID: PMC4530054.
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 PLoS One. 2015 Aug 7;10(8):e0135142. doi: 10.1371/journal.pone.0135142. eCollection 2015. PMCID: PMC4529177
- 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
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 Jun 26;10(6):e1004212. PMCID: PMC4072785
- 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
Bramwell KC, Ma Y, Weis JH, Chen X, Zachary JF, Teuscher C, Weis JJ. Lysosomal beta-glucuronidase regulates Lyme and rheumatoid arthritis severity. 2014. J Clin Invest 124:311-320. PMCID:PMC3871255
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
- 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
- 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
- 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
- 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