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.

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Localized elevation in Type I IFN has been uniquely linked to the severe Lyme arthritis that develops in C3H mice infected with the spirochete Borrelia burgdorferi. In this study, the dynamic interactions that result in generation of these responses were further examined in C3H mice carrying the Type I IFN receptor gene ablation, which effectively blocks all autocrine/paracrine signaling crucial to induction of downstream effectors. Reciprocal radiation chimeras between C3H and IFNAR1−/− mice implicated both radiation-sensitive and radiation-resistant cells of the joint tissue in the pro-arthritic induction of Type I IFN. Ex vivo analysis of cells from the naïve joint revealed CD45+ cells residing in the tissue to be uniquely capable of initiating the Type I IFN response to B. burgdorferi. Type I IFN responses were analyzed in real time by lineage sorting of cells from infected joint tissue. This demonstrated that myeloid cells, endothelial cells, and fibroblasts were responsible for propagating the robust IFN response, which peaked at Day 7 post infection and rapidly resolved. Endothelial cells and fibroblasts were the dominant sources of IFN signature transcripts in the joint tissue. Fibroblasts were also the major early source of chemokines associated with PMN and monocyte/macrophage infiltration, thus providing a focal point for arthritis development. These findings suggest joint-localized interactions among related and unrelated stromal, endothelial, and myeloid cell lineages that may be broadly applicable to understanding the pathogeneses of diseases associated with type I IFN signature, including systemic lupus erythematosus and some rheumatoid arthritides.

Background Sodalis glossinidius, a maternally transmitted bacterial endosymbiont of tsetse flies (Glossina spp.), uses an acylated homoserine lactone (AHL)-based quorum sensing system to modulate gene expression in accordance with bacterial cell density. The S. glossinidius quorum sensing system relies on the function of two regulatory proteins; SogI (a LuxI homolog) synthesizes a signaling molecule, characterized as N-(3-oxohexanoyl) homoserine lactone (OHHL), and SogR1 (a LuxR homolog) interacts with OHHL to modulate transcription of specific target genes.Methodology/Principal FindingsWe used a tiling microarray to analyze the S. glossinidius transcriptome in the presence and absence of exogenous OHHL. The major finding is that OHHL increases transcription of a large number of genes that are known to be involved in the oxidative stress response. We also show that the obligate symbiont of the rice weevil, Sitophilus oryzae (SOPE), maintains copies of the quorum sensing regulatory genes that are found in S. glossinidius. Molecular evolutionary analyses indicate that these sequences are evolving under stabilizing selection, consistent with the maintenance of their functions in the SOPE symbiosis. Finally, the expression studies in S. glossinidius also reveal that quorum sensing regulates the expression of a cryptic, degenerate gene (carA) that arose from an ancient deletion in the last common ancestor of S. glossinidius and SOPE.Conclusions/SignificanceThis oxidative stress response is likely mandated under conditions of dense intracellular symbiont infection, when intense metabolic activity is expected to generate a heavy oxidative burden. Such conditions are known to arise in the bacteriocytes of grain weevils, which harbor dense intracellular infections of symbiotic bacteria that are closely related to S. glossinidius. The presence of a degenerate carA sequence in S. glossinidius and SOPE indicates the potential for neofunctionalization to occur during the process of genome degeneration.