From forest floor to doctor's office: the immunological journey of Borrelia burgdorferi through vertebrate hosts.

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most prevalent vector-borne infection in the Northern Hemisphere and continues to expand geographically. Although B. burgdorferi has a streamlined genome and minimal virulence repertoire, it establishes persistent infection through coordinated modulation of mammalian host immune responses. Here, we synthesize recent advances in the immunobiology of B. burgdorferi using a stage-structured framework that traces a tick-mediated vertebrate infection through systemic dissemination, tissue colonization, and chronic immune engagement. Emphasis is placed on post-2020 insights enabled by intravital imaging, single-cell transcriptomics, spatial profiling, and systems immunology, which have refined our understanding of endothelial transmigration, tissue-specific immune conditioning, disruption of germinal center responses, and failure of sterilizing immunity. We highlight how antigenic variation at the vls locus, complement evasion, and coordinated adhesin networks support dissemination and long-term tissue residency, while adaptive immune responses are redirected toward extrafollicular, non-sterilizing trajectories. These immune strategies differentially shape infection outcomes across host species, supporting asymptomatic persistence in reservoir hosts while driving inflammatory disease in humans. The review further examines antigen persistence, immune stalemate, and post-treatment inflammatory sequelae, integrating translational advances in diagnostics and prevention. By integrating an ecological context with mechanistic immunology and clinical insight, this review presents a contemporary framework for understanding how immune modulation by B. burgdorferi across spatial and temporal scales shapes host-pathogen coevolution and informs improved diagnostic strategies, vaccine development, and therapeutic intervention.