Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most prevalent arthropod-borne illness in the United States and remains a clinical and social challenge. The spectrum of disease severity among infected patients suggests that host genetics contribute to pathogenic outcomes, particularly in patients who develop arthritis. Using a forward genetics approach, we identified the lysosomal enzyme β-glucuronidase (GUSB), a member of a large family of coregulated lysosomal enzymes, as a key regulator of Lyme-associated arthritis severity. Severely arthritic C3H mice possessed a naturally occurring hypomorphic allele, Gusbh. C57BL/6 mice congenic for the C3H Gusb allele were prone to increased Lyme-associated arthritis severity. Radiation chimera experiments revealed that resident joint cells drive arthritis susceptibility. C3H mice expressing WT Gusb as a transgene were protected from severe Lyme arthritis. Importantly, the Gusbh allele also exacerbated disease in a serum transfer model of rheumatoid arthritis. A known GUSB function is the prevention of lysosomal accumulation of glycosaminoglycans (GAGs). Development of Lyme and rheumatoid arthritis in Gusbh-expressing mice was associated with heightened accumulation of GAGs in joint tissue. We propose that GUSB modulates arthritis pathogenesis by preventing accumulation of proinflammatory GAGs within inflamed joint tissue, a trait that may be shared by other lysosomal exoglycosidases.
Kenneth K.C. Bramwell, Ying Ma, John H. Weis, Xinjian Chen, James F. Zachary, Cory Teuscher, Janis J. Weis
(A) Transgenic overexpression of mouse Gusbb by a pCAGGS-based mammalian expression construct (58). (B) Five founders exhibited elevated GUSB serum activity relative to a β-galactosidase internal control. (C) C3H GusbTg mice developed markedly less severe Lyme arthritis than WT C3H controls (n = 10 for B6 and C3H control groups, n = 22 total GusbTg progeny from 4 different founders, no. 38 was infertile; overall P < 0.001). Significance assessed by 1-way ANOVA and Bonferroni’s post test (ankle swelling) or nonparametric Kruskal-Wallis test and Dunn’s multiple comparison test (histopathology). **P < 0.01; ***P < 0.001.