Contributed by Christine Jacobs-Wagner, May 11, 2019 (sent for review March 14, 2019; reviewed by Thomas G. Bernhardt and Justin D. Radolf)
Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne disease in North America. If early infection is untreated, it can result in late-stage manifestations, including arthritis. Although antibiotics are generally effective at all stages of the disease, arthritis may persist in some patients for months to several years despite oral and intravenous antibiotic treatment. Excessive, dysregulated host immune responses are thought to play an important role in this outcome, but the underlying mechanisms are not completely understood. This study identifies the B. burgdorferi peptidoglycan, a major component of the cell wall, as an immunogen likely to contribute to inflammation during infection and in cases of postinfectious Lyme arthritis.
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 (PGBb) that is not recycled during cell-wall turnover. Instead, this pathogen sheds PGBb fragments into its environment during growth. Patients with LA mount a specific immunoglobulin G response against PGBb, which is significantly higher in the synovial fluid than in the serum of the same patient. We also detect PGBb 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 PGBb. In addition, systemic administration of PGBb in BALB/c mice elicits acute arthritis. Altogether, our study identifies PGBb 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 PGBb fragments during growth suggests a potential role for PGBb in the immunopathogenesis of other Lyme disease manifestations.
↵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: .
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.
- The authors declare no conflict of interest.
- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1904170116/-/DCSupplemental.
Copyright © 2019 the Author(s). Published by PNAS.
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