Integrative diagnostic modeling identified a 12-analyte panel of vascular and metabolic markers that distinguished Lyme patients from controls with high accuracy (AUC = 0.92).

Tissue-derived signals dominate circulating profiles. Plasma cytokines, chemokines, and metabolic changes primarily arose from skin-resident fibroblasts, keratinocytes, and endothelial cells at the site of infection, not PBMCs—highlighting the need for tissue-based diagnostics and interventions.

Temporal analysis revealed distinct phases of immune resolution: fast-resolving inflammatory cytokines peaking early and declining rapidly, and slow-resolving inhibitory proteins persisting for months, suggesting a sustained immunosuppressive milieu.

Vascular involvement emerged as a central feature of acute Lyme disease. Plasma profiles revealed two opposing endothelial circuits: one inflammatory and disruptive (IFN-γ → CXCL9/10/11 → endothelial stress), the other protective (S1P, β-hydroxybutyrate, ANGPT1 → vascular stability).

We found that immune responses in Lyme disease are highly compartmentalized. Robust immune and vascular signals were detected in plasma, while PBMCs remained largely quiescent. This local-systemic disconnect may underlie limitations of current antibody-based diagnostics.

We conducted a longitudinal multiomic study of 49 Lyme disease patients and matched controls, integrating plasma proteomics, metabolomics, PBMC profiling (flow cytometry + scRNA-Seq validation), skin lesion meta-analysis, and clinical phenotyping.