Teuscher and Utah Colleagues Identify Lyme Arthritis Susceptibility Gene
- By Jennifer Nachbur
A genetic “hunt” begun nearly a quarter century ago by University of Vermont immunogeneticist Cory Teuscher, Ph.D., and University of Utah microbiologist Janis Weis, Ph.D., has led to a “buried treasure” in the field of Lyme disease research: confirmation that a hypomorphic allele of the beta-glucuronidase gene (Gusbh) is independently responsible for more severe forms of Lyme arthritis in a mouse model. These findings were published December 16, 2013 in the online-first edition of the Journal of Clinical Investigation and are also featured in the January 2014 issue of JCI Impact.
More than 30,000 cases of Lyme disease are reported each year. This disease, caused by the bacterium Borrelia burgdorferi, is transferred to humans through a tick bite. Within months to years, individuals with untreated disease – and up to 10 percent of those who have been treated – can develop arthritis that can last for years after infection. According to the Centers for Disease Control and Prevention, Lyme arthritis manifests differently than other causes of arthritis, with severe joint pain and swelling, particularly in the knees.
Teuscher, an expert in the genetics of susceptibility to infectious and autoimmune disease, and Weis, who has been conducting National Institutes of Health-funded research on a Lyme disease infection and inflammatory response for more than two decades, initially met at a scientific retreat when Teuscher was on the faculty at Brigham Young University, and began collaborating shortly thereafter.
“It was a perfect example of a true interdisciplinary approach – his genetics expertise, my mouse model,” says Weis, the paper’s senior author and a professor of pathology at University of Utah.
Weis developed a Lyme disease mouse model that allowed Teuscher and colleagues to map the genes linked to Lyme arthritis.
“We were hoping to identify genes and physiological pathways responsible for the differences in arthritis severity, with an eventual goal of identifying potential therapeutic interventions,” says Weis in a University of Utah press release.
The researchers found that six different genetic regions were linked to disease severity, and through an iterative process of physical mapping using congenic mice, proceeded to identify the principal gene responsible for more severe arthritis in their model.
“GUSB is a gene with a normal function in a cell – to cleave sugar residue,” explains Teuscher, a professor of medicine at the University of Vermont College of Medicine.
But a defect in this protein, he and the research team discovered, is a key regulator of disease severity. Moreover, they also found that this same allele plays a similar role in a mouse model of rheumatoid arthritis. Thus, Gusbh is another example of a shared immunolopathology disease gene, a class of immune disease-related genes whose existence Teuscher first hypothesized in the mid-1980s. In fact, he, Weis and colleagues explain, enzymes called glycosaminoglycans or GAGs, can be attached to GUSB, and have a normal turnover process. However, in the mice with the Gusbh, more GAGs were present in the joints, exacerbating the arthritis.
“We suspect that attributes specific to the infected individual may contribute to differences in Lyme disease and rheumatoid arthritis outcomes,” says Teuscher.
Kenneth Bramwell, Ph.D., first author on the study and a postdoctoral fellow in Weis’ lab, contributed significantly to the work that led to the group’s Gusbh discovery. Other co-authors on the study include Ying Ma, M.S., research associate, John Weis, Ph.D., professor of pathology, and Xinjian Chen, M.D., Ph.D., associate professor of pathology, University of Utah; and James Zachary, D.V.M., Ph.D., professor emeritus of pathobiology, University of Illinois.
Link to the Journal of Clinical Investigation study here.
This work was funded by National Institutes of Health grants R01AR43521, R01AI32223, T32AI055434, R01NS061014, R01AI042747, R01NS060901, R01NS036526, and the Arthritis Foundation.
Research reported in this article/press release was supported by the National Institute of Allergy and Infectious Diseases (NIAID) R01AI32223, T32AI055434, R01AI042747, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R01AR43521, National Institute of Neurological Disorders and Stroke (NINDS) R01NS061014, R01NS060901, R01NS036526, and the Arthritis Foundation.