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) Advanced congenic lines identify regulatory subintervals within Bbaa2. Each row represents the genetic makeup of 1 congenic mouse line across the Bbaa2 interval (120.3 to 141.2 Mb) on mouse chromosome 5. White and black portions of each row represent areas inherited from the B6 or C3H background, respectively. Ankle swelling measurements taken 4 weeks after B. burgdorferi infection (n = 12 to 35 mice per group; overall P < 0.0001). Significance of cosegregation (right) between ankle swelling and blinded scores of joint histopathology and PMN infiltration, assessed by 1-tailed Mann-Whitney test. (B) Inheritance of the Gusb polymorphism among strains included in the Sanger SNP resequencing database. (C) C3H mice and congenics carrying the Gusbh allele exhibited enzymatic hypomorphism in serum and bone marrow–derived macrophage cell extracts and supernatants (n = 4). (D) CBA/Ca expressed near normal serum GUSB activity, while CBA/J shared the C3H GUSB hypomorphism. (E) CBA/J developed severe Lyme arthritis, while CBA/Ca were resistant (n = 5 [B6 and C3H] and 10 [CBA substrains] mice in each group; overall P < 0.0001). Significance assessed by 1-way ANOVA followed by Dunnet’s multiple comparison test versus B6 (A and E) or Bonferroni’s post test (C and D). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.