https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009256

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

Timothy Casselli , Ali Divan, Emilie E. Vomhof-DeKrey, Yvonne Tourand, Heidi L. Pecoraro, Catherine A. Brissette

Published: February 1, 2021

https://doi.org/10.1371/journal.ppat.1009256

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.

Author summary

Lyme disease is a result of inflammation-induced tissue pathology in response to infection with Borrelia burgdorferi. A major barrier to progress in understanding the neurologic manifestations of Lyme disease has been a lack of a tractable laboratory animal model to evaluate the mechanisms of central nervous system pathogenesis. Here we addressed this barrier by characterizing for the first time the kinetics of Borrelia burgdorferi colonization in the meninges of laboratory mice, and the resulting immune responses in both the meninges and brain. We demonstrate the presence and kinetics of live spirochetes in the meninges of infected mice, and show that meningeal infection is a general phenomenon shared by several Lyme disease Borrelia species. Meningeal colonization was associated with infiltrating leukocytes and local changes in immune response genes previously shown to be associated with Lyme disease pathology. Intriguingly, we show increased expression of immune response genes including those involved in antigen presentation in the brain, despite a lack of detectable infiltrating bacteria or leukocytes in this tissue. Overall, these findings characterize the central nervous system responses to Borrelia burgdorferi infection in a cost-effective and genetically robust animal model, and provide insights into the mechanisms of neuropathologies associated with Lyme disease.

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**Comment**

Although this was in mice, patients the world over have experienced inflammation in the brain, including yours truly.  I wondered if I’d ever have a day without head and neck pain that honestly felt like a horse kicked me.  Thankfully, integrated, persistent treatment resolved this issue.  I also have met numerous patients who ended up with a Chiari diagnosis due to the effects of undiagnosed Lyme/MSIDS, so the results of this inflammation can be severe:  https://madisonarealymesupportgroup.com/2016/04/02/chiari/

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