Persistent Borrelia burgdorferi Peptidoglycan in Postinfectious Lyme Arthritis: Innate Immune Sensing and Translational Implications

Lyme arthritis (LA) is the late articular manifestation of Borrelia burgdorferi infection. It is ordinarily treated successfully with appropriate antibiotic therapy. In a subset of patients, however, synovitis persists for months to years after treatment, despite presumed eradication of the spirochete. This state is termed postinfectious, or antibiotic-refractory, LA, and its cellular and molecular basis remains incompletely defined. It is distinct from post-treatment Lyme disease syndrome (PTLDS), which is defined by persistent subjective symptoms without objective joint inflammation. Attention has increasingly turned to the non-canonical peptidoglycan (PG) of B. burgdorferi. Three questions are central: what becomes of this material during bacterial growth, whether it persists within the joint after antimicrobial treatment, and whether it can engage innate immune sensing pathways such as NOD2. Whether such sensing occurs in the human joint has yet to be established. This narrative review synthesizes the available human, murine, and in vitro mechanistic evidence on four topics: B. burgdorferi PG biology, PG processing in both the bacterium and the host, the innate mechanisms of PG recognition, and the intersection of these pathways with adaptive autoimmune mechanisms in postinfectious LA. Throughout, findings established in patients are distinguished from inferences drawn from murine models and from hypotheses that remain unsupported by patient-level data. Human evidence is limited to detection of PG in synovial fluid from closely related research groups and is not independently replicated, together with genetic, immunologic, and tissue studies that do not themselves address PG. Findings such as PG tropism for the liver and NOD2 sensing derive from murine and in vitro systems. No study has shown that persistent PG or NOD2 signaling causes human postinfectious synovitis. The authors then consider the translational implications for diagnostic, prognostic, and anti-inflammatory or PG-directed strategies as hypotheses.