Longitudinal serum proteomics identifies candidate immune, coagulation, and metabolic signatures associated with post-treatment Lyme disease

Lyme disease is the most common vector-borne infection in the US. While most patients return to health (RTH) after antibiotics, 10–20% develop functionally impairing pain and neurocognitive symptoms, termed post-treatment Lyme disease (PTLD). Mechanisms underlying PTLD remain unclear. Serum was collected at acute infection (Visit 1 [V1]) and six months after antibiotics (Visit 5 [V5]) from patients with RTH (n = 16) and PTLD (n = 16), and 4 healthy controls (HC). We performed longitudinal serum proteomics analysis (18-plex TMT LC–MS/MS) in adults with erythema migrans enrolled in a prospective study. Subsequently, differential expression, KEGG pathway enrichment, and Weighted Gene Co-expression Network Analysis (WGCNA) analyses were conducted to identify outcome-associated protein pathways/modules and their association with clinical traits and symptom domains. Ranked KEGG pathway-enrichment analysis showed significant enrichment of the complement and coagulation cascades pathway in PTLD relative to RTH at V1, followed by a significant decrease from V1 to V5 within PTLD. No significant longitudinal change was observed in RTH (V5 versus V1), and at V5, PTLD vs RTH no longer differed significantly. WGCNA identified seven modules; four (M4-7, associated with acute phase proteins, complement/coagulation, lipid metabolism) were overexpressed in PTLD vs RTH at V1. M1 (proteasome/cytoskeletal) was reduced in PTLD at V1. PTLD is characterized by an acute-phase complement–coagulation proteomic signature associated with subsequent clinical outcome that attenuates over longitudinal follow-up. These findings suggest differential resolution of acute host-response pathways between participants who subsequently develop PTLD and those who return to health.