Persistent Borrelia burgdorferi protein antigen in CD16⁺ monocytes is associated with monocyte-skewed immune dysregulation in post-treatment Lyme disease syndrome (PTLDS)

Post-treatment Lyme disease syndrome (PTLDS) is characterized by persistent symptoms after antibiotic therapy for Borrelia burgdorferi infection. The mechanisms underlying these symptoms remain incompletely understood and have been attributed to ongoing low-level infection, autoimmunity, or immune dysregulation driven by residual bacterial antigens. We investigated whether Borrelia burgdorferi protein antigen persists in long-lived monocyte subsets in PTLDS patients and is associated with broader immune dysregulation. CD14CD16 monocytes from 10 patients with PTLDS were analyzed by mass spectrometry; plasma from all 10 was profiled on a 14-plex cytokine panel against 50 healthy donors; PBMCs from 6 patients (3 antigen-positive and 3 antigen-negative) underwent RT-qPCR and bulk RNA-seq with immune-compartment profiling. FlaB and OspC were detected in CD14CD16 monocytes months to years after treatment, whereas Borrelia burgdorferi transcript was not detected. Plasma IFN-{gamma} exceeded the healthy donor median in all 10 participants. Antigen-positive samples showed an antigen-associated inflammatory transcriptional profile, including increased TNFSF14/LIGHT, GSDMD, GBP5, and KCNJ2 expression, together with a compartment-level pattern of monocyte-skewed myeloid reconfiguration, higher neutrophil-related features, and selective T-cell-state changes. These findings link residual Borrelia burgdorferi protein in CD14CD16 monocytes to monocyte-skewed immune remodeling in PTLDS, paralleling observations in long COVID and supporting a model in which post-infectious syndromes are sustained by antigen-fueled immune remodeling rather than ongoing infection.