Abstract

Lyme disease is a multisystem disorder caused by the spirochete Borrelia burgdorferi. A common late-stage complication of this disease is oligoarticular arthritis, often involving the knee. In ∼10% of cases, arthritis persists after appropriate antibiotic treatment, leading to a proliferative synovitis typical of chronic inflammatory arthritides. Here, we provide evidence that peptidoglycan (PG), a major component of the B. burgdorferi cell envelope, may contribute to the development and persistence of Lyme arthritis (LA). We show that B. burgdorferi has a chemically atypical PG (PG^Bb) that is not recycled during cell-wall turnover. Instead, this pathogen sheds PG^Bb fragments into its environment during growth. Patients with LA mount a specific immunoglobulin G response against PG^Bb, which is significantly higher in the synovial fluid than in the serum of the same patient. We also detect PG^Bb in 94% of synovial fluid samples (32 of 34) from patients with LA, many of whom had undergone oral and intravenous antibiotic treatment. These same synovial fluid samples contain proinflammatory cytokines, similar to those produced by human peripheral blood mononuclear cells stimulated with PG^Bb. In addition, systemic administration of PG^Bb in BALB/c mice elicits acute arthritis. Altogether, our study identifies PG^Bb as a likely contributor to inflammatory responses in LA. Persistence of this antigen in the joint may contribute to synovitis after antibiotics eradicate the pathogen. Furthermore, our finding that B. burgdorferi sheds immunogenic PG^Bb fragments during growth suggests a potential role for PG^Bb in the immunopathogenesis of other Lyme disease manifestations.

Footnotes

• ↵¹Present address: Fralin Life Sciences Institute, Department of Biochemistry, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24061.

• ↵²Present address: Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226.

• ↵³To whom correspondence may be addressed. Email: christine.jacobs-wagner@yale.edu.

• Author contributions: B.L.J. and C.J.-W. designed research; B.L.J., R.B.L., Z.A.K., J.B., K.S., C.J.B., J.G., P.S., W.V., L.K.B., and A.C.S. performed research; B.L.J., R.B.L., Z.A.K., S.K.G., and W.V. analyzed data; and B.L.J., Z.A.K., and C.J.-W. wrote the paper with assistance from all authors.

• Reviewers: T.G.B., Harvard Medical School; and J.D.R., University of Connecticut Health Sciences Center.

Copyright © 2019 the Author(s). Published by PNAS.