Proteoglycans and Lyme Disease: Molecular Interfaces in Adhesion, Tissue Tropism, and Therapeutic Discovery

Abstract

Lyme disease, caused by spirochetes of the Borrelia burgdorferi sensu lato complex, is a multisystem tick‐borne infection in which bacterial dissemination depends on interactions with host cells and the extracellular matrix (ECM). Proteoglycans (PGs), composed of core proteins modified with glycosaminoglycan (GAG) chains, are abundant and structurally diverse components of these tissues. B. burgdorferi exploits PGs and GAGs through several surface adhesins, including decorin‐binding proteins A and B (DbpA and DbpB), Borrelia glycosaminoglycan‐binding protein (Bgp), BBK32, and other GAG‐interacting proteins. Recognition of decorin provides a particularly strong mechanistic link between bacterial adhesion and colonization of collagen‐rich connective tissues. Variability in borrelial adhesins together with heterogeneity in host GAG structure may further influence tissue tropism and disease manifestations. This prospective review examines the PG–Lyme borreliae interface as an active determinant of Lyme disease pathogenesis and highlights emerging approaches, including glycomics, structurally defined GAG libraries, glycan microarrays, surface plasmon resonance, and structural biology, for defining these interactions. We also discuss the potential of GAG‐based molecular decoys and inhibitors to disrupt Lyme borreliae adhesion and colonization.