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) GusbNull mice do not exhibit a defect in host defense. The observed difference between B6 and C3H genetic backgrounds in heart bacterial burden has been previously described (59). (B) Serum GUSB activity of infected B6 and C3H controls, GusbNull homozygotes, and GusbNull heterozygous littermates (n = 5 to 6 per group). (C) Arthritis severity measurements of GusbNull homozygotes, heterozygous littermates, and WT B6 and C3H controls (n = 5 to 6 per group; overall P < 0.0001). (D and E) Arthritis severity measurements of B6.C3H-Bbaa2 and B6.C3H-Gusbh heterozygotes were statistically indistinguishable from B6 control animals (n = 5 per group; overall P < 0.001). Significance assessed by 1-way ANOVA followed by Bonferroni’s multiple comparison test versus B6. *P < 0.05; ***P < 0.001; ****P < 0.0001.