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.
Highlights
Lyme disease (LD), which is caused by infection with the bacterial pathogen Borrelia burgdorferi and related species, is a prevalent and continually emerging vector-borne disease throughout North America and Europe [1,2]
Based on our previous finding that B. burgdorferi isolate 297 (Bb_297) colonized the dura mater of C3H mice during late disseminated infection (75 days post-infection) [33], we set out to determine the kinetics of dura mater colonization during early and subacute infection
Whole-mount dura mater stained with anti-B. burgdorferi antibodies from uninfected mice or 3-day infected mice did not show the presence of intact spirochetes, whereas spirochetes were identified at all later infection timepoints (Fig 2)
Summary
Lyme disease (LD), which is caused by infection with the bacterial pathogen Borrelia burgdorferi and related species, is a prevalent and continually emerging vector-borne disease throughout North America and Europe [1,2]. Disseminated infection can lead to a number of subacute and persistent inflammatory pathologies affecting the joints (arthritis), heart (carditis and heart block), and nervous systems including the central nervous system (CNS) [3,4,5,6]. Inbred laboratory mice have served as effective models to characterize B. burgdorferi infection kinetics, as well as the host immune responses involved in pathogen burden control and inflammatory pathology. After initial infection by either needle inoculation or tick transmission, spirochetes disseminate throughout the animal and colonize peripheral tissues including skin, joints, and heart [7,8]. Infection of disease-susceptible C3H mice results in subacute arthritis and carditis characterized by joint swelling and histopathological manifestations similar to human disease including leukocyte infiltration [9,10]
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