A murine model of Lyme disease demonstrates that Borrelia burgdorferi colonizes the dura mater and induces inflammation in the central nervous system

Abstract

Lyme disease, which is caused by infection with Borrelia burgdorferi and related species, can lead to inflammatory pathologies affecting the joints, heart, and nervous systems including the central nervous system (CNS). Inbred laboratory mice have been used to define the kinetics of B. burgdorferi infection and host immune responses in joints and heart, however similar studies are lacking in the CNS of these animals. A tractable animal model for investigating host-Borrelia interactions in the CNS is key to understanding the mechanisms of CNS pathogenesis. Therefore, we characterized the kinetics of B. burgdorferi colonization and associated immune responses in the CNS of mice during early and subacute infection. Using fluorescence-immunohistochemistry, intravital microscopy, bacterial culture, and quantitative PCR, we found B. burgdorferi routinely colonized the dura mater of C3H mice, with peak spirochete burden at day 7 post-infection. Dura mater colonization was observed for several Lyme disease agents including B. burgdorferi, B. garinii, and B. mayonii. RNA-sequencing and quantitative RT-PCR showed that B. burgdorferi infection was associated with increased expression of inflammatory cytokines and a robust interferon (IFN) response in the dura mater. Histopathologic changes including leukocytic infiltrates and vascular changes were also observed in the meninges of infected animals. In contrast to the meninges, we did not detect B. burgdorferi, infiltrating leukocytes, or large-scale changes in cytokine profiles in the cerebral cortex or hippocampus during infection; however, both brain regions demonstrated similar changes in expression of IFN-stimulated genes as observed in peripheral tissues and meninges. Taken together, B. burgdorferi is capable of colonizing the meninges in laboratory mice, and induces localized inflammation similar to peripheral tissues. A sterile IFN response in the absence of B. burgdorferi or inflammatory cytokines is unique to the brain parenchyma, and provides insight into the potential mechanisms of CNS pathology associated with this important pathogen.

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

“…Evidence now exists, from the results of experiments in both murine and non-human primate models, that persisting B. burgdorferi can be metabolically active, expressing certain bacterial genes and inducing gene expression changes in the infected host, despite being non-culturable following antibiotic treatment (22,(37)(38)(39). In one model, the spirochetes localized to the dura mater of the brain, associated with large-scale changes in gene expression of pro-inflammatory cytokines and chemokines (40,41). Although there was no evidence of direct infection of the brain itself in this model, certain brain tissues expressed genes related to interferon signaling pathways.…”

Lyme Disease IgG N-linked Glycans Contrast the Canonical Inflammatory Signature

“…Antibiotic treatment for LD in the acute phase is often curative [9–12]. However, untreated patients and a subset of treated patients progress to disseminated disease [13, 14], Disseminated disease can result in facial nerve palsy [15], Lyme Carditis [16], Lyme Arthritis [17], Lyme Neuroborreliosis [18, 19], and long-term disability [20, 21]. Persistent symptoms are reported by 10-20% of patients diagnosed and treated during the acute phase of LD.…”

Borreliae Part 1: Borrelia Lyme Group and Echidna-Reptile Group

“…The loss of plasmids has been associated with the inability of the microorganism to infect laboratory animals, suggesting that plasmids code for key proteins involved in virulence [160]. Nevertheless, recently a murine model to study Lyme disease has been developed to investigate the potential mechanisms of central nervous system pathologies associated with Lyme disease [161].…”