loading . . . Multiomics Reveals Compartmentalized Immune Responses and Tissue-Vascular Signatures in Lyme Disease Lyme disease (LD) is growing in incidence, with nearly 500,000 cases diagnosed annually in the United States. Despite treatment, some patients experience persistent symptoms. The immune mechanisms underlying LD remain poorly understood. We conducted a multiomic longitudinal analysis of 49 LD patients and matched controls, integrating plasma proteomics, metabolomics, PBMC immunophenotyping, and a meta-analysis of skin lesions. We identified compartmentalized immune responses in acute LD, with coordinated alterations in circulating plasma proteins and metabolites linked to endothelial barrier stability, metabolic reprogramming, and symptom severity, predominantly traced to tissue and vascular immune processes at the site of infection. In contrast, PBMCs remained largely quiescent, revealing a disconnect between localized tissue responses and systemic immunity. These findings provide novel insights into LD pathophysiology and highlight the potential for diagnostics leveraging tissue and vascular immune markers detectable in blood. They also provide a resource for biomarker discovery and predictive modeling to improve LD management. ### Competing Interest Statement CR, AB, HH, LP, MEB, DC, CL, ASA, BS, KS, PT, KW, NR, LH, and NS declare no competing financial interests. GPW reports receiving research grants from Biopeptides Corp., has served as an expert witness in malpractice cases involving Lyme disease, and is an unpaid board member of the non-profit American Lyme Disease Foundation. United States Department of Defense, https://ror.org/0447fe631, W81XWH2110664 Wilke Family Foundation Steven and Alexandra Cohen Foundation Global Lyme Alliance, https://ror.org/05tzrqq19 https://www.biorxiv.org/content/10.1101/2025.05.27.656061v1
