Scholarly Emphasis: Lyme Arthritis
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.
Weis also serves as the director of the Microbial Pathogenesis Training Grant, which sponsors the Microbial Pathogenesis Seminar Series.