The peptidoglycan of <i>Borrelia burgdorferi</i> can persist in discrete tissues and cause systemic responses consistent with chronic illness

Persistent symptoms after an acute infection is an emerging public health concern, but the pathobiology of such conditions is not well understood. One possible scenario involves the persistence of lingering antigen. We have previously reported that patients with postinfectious Lyme arthritis often harbor the peptidoglycan (PG) cell wall of <i>Borrelia burgdorferi</i>, the Lyme disease agent, in the synovial fluid of their inflamed joints after treatment. However, it is not yet known how <i>B. burgdorferi</i> PG persists, in what form, or if it may play a role in other postinfectious complications after Lyme disease. Using a murine model, we developed a real-time in vivo system to track <i>B. burgdorferi</i> PG as a function of cell wall chemistry and validated our findings using both molecular and cellular approaches. Unlike typical bacterial PG, the unique chemical properties of polymeric <i>B. burgdorferi</i> PG drive murine liver accumulation, where the cell wall material persists for weeks. Kupffer cells and hepatocytes phagocytose and retain <i>B. burgdorferi</i> PG and, although liver occupancy coincides with minimal pathology, both organ-specific and secreted protein profiles produced under these conditions bear some similarities to reported proteins enriched in patients with chronic illness after acute infection. Moreover, transcriptomic profiling indicated that <i>B. burgdorferi</i> PG affects energy metabolism in peripheral blood mononuclear cells. Our findings provide mechanistic insights into how a pathogenic molecule can persist after agent clearance, potentially contributing to illness after infection.