Immune Response to Borrelia: Lessons from Lyme Disease Spirochetes

Abstract

The mammalian host responds to infection with Borrelia spirochetes through a highly orchestrated immune defense involving innate and adaptive effector functions aimed toward limiting pathogen burdens, minimizing tissue injury, and preventing subsequent reinfection. The evolutionary adaptation of Borrelia spirochetes to their reservoir mammalian hosts may allow for its persistence despite this immune defense. This review summarizes our current understanding of the host immune response to B. burgdorferi sensu lato, the most widely studied Borrelia spp. and etiologic agent of Lyme borreliosis. Pertinent literature will be reviewed with emphasis on in vitro, ex vivo and animal studies that influenced our understanding of both the earliest responses to B. burgdorferi as it enters the mammalian host and those that evolve as spirochetes disseminate and establish infection in multiple tissues. Our focus is on the immune response of inbred mice, the most commonly studied animal model of B. burgdorferi infection and surrogate for one of this pathogen's principle natural reservoir hosts, the white-footed deer mouse. Comparison will be made to the immune responses of humans with Lyme borreliosis. Our goal is to provide an understanding of the dynamics of the mammalian immune response during infection with B. burgdorferi and its relation to the outcomes in reservoir (mouse) and non-reservoir (human) hosts.Curr. Issues . caister.com/cimb caister.com/cimb 145 Curr. Issues Mol. Biol. Vol. 42 Immune Response to Borrelia Bockenstedt et al.

Report of the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee of the HHS Tick Borne Disease Working Group

“…Borrelia burgdorferi establishes persistent and non-resolving infections in fully immunocompetent mice, strongly suggesting that the bacteria have developed multiple and likely complex immune evasion strategies (9,11). Both innate and adaptive immune responses control B. burgdorferi in these hosts [reviewed in (12)]. These species rarely, and only transiently, develop clinical manifestations of disease, without an obvious correlation between the tissue-loads of B. burgdorferi and clinical manifestations, except in severely immunocompromised mice, for example those that lack T and B cells (SCID mice), or the ability to activate innate immune effectors because of deletions in the toll-like receptor (TLR) 2 or TLR adaptor protein MyD88 (13)(14)(15).…”

“…This movement can be tracked in real time in mice with the use of multiphoton/confocal microscopy and fluorescently labeled B. burgdorferi . Ongoing imaging analysis revealed that the number of spirochetes peaked around 7–10 days after infection ( 12 ). This peak was followed by a dramatic drop in spirochete numbers, where they persisted for the duration of the experiment.…”

“…Spirochetes often tend to reside in the dermis. Of the various resident immune response cells, Langerhans cells were not as effective as macrophages, or other dendritic cells or neutrophils in phagocytosing the bacteria, as spirochetes move up to 80 times faster than any of these immune response cells ( 12 ). Neutrophils responded the fastest, but after a certain point, they stop responding, leaving a number of viable spirochetes.…”

“…Synovial fluid from some human patients with Lyme arthritis, many of whom had received 1–3 months of antibiotic therapy, had high levels of detectible peptidoglycan, as well as anti-peptidoglycan antibodies, despite a lack of any evidence of ongoing infection after antibiotic therapy ( 42 ). Thus, it appears that B. burgdorferi peptidoglycan might be a persistent antigen in Lyme arthritis ( 12 ). Ongoing research is being conducted to determine whether B. burgdorferi peptidoglycan plays a role in the pathogenesis and pathophysiology of neuroborreliosis or of persistent Lyme disease other than previously treated Lyme arthritis.…”

Single-cell immunophenotyping of the skin lesion erythema migrans identifies IgM memory B cells

“…Borreliella spirochetes are widely held to be extracellular pathogens for which phagocytes, antibody and complement are critical for host defense (4). Bb-specific antibodies prevent infection in both animal models and humans and contribute to a reduction in pathogen burden and resolution of disease manifestations in mouse models (4). In humans, a robust circulating plasmablast response was found to correlate with more rapid resolution of LD symptoms after antibiotic treatment for EM (5).…”