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.
Technically one could say this isn’t the brain. It’s the outer layer called the meninges – of which, the dura mater is one layer. Regardless, this inflammation caused by infections can cause swelling, pain, and so much more. It’s also why some Lyme/MSIDS patients have been diagnosed with Chiari.
Overall, we report that B. burgdorferi routinely colonizes the meninges in laboratory mice during early and subacute infection, and induces similar localized inflammatory gene expression profiles as other peripheral tissues as well as histopathological changes.
Overall, the findings reported in this study are significant, as the lack of a tractable animal model has hindered our understanding of host-pathogen interactions in the CNS during B. burgdorferi infection. Our results provide insight into potential mechanisms of CNS pathologies associated with Lyme disease, and describe a model system that will allow for future studies evaluating the bacterial, host, and environmental factors that can contribute to the severity of CNS involvement during B. burgdorferi infection. Such studies are critical for the development and implementation of novel prophylactic and therapeutic interventions for this important disease.
The discussion section mentioned something that’s always interested me: the location of the tick bite or injection site. The authors state that although they were able to “readily culture spirochetes from the blood of all mice at day 7 post-infection, dura spirochetes were rarely detected in mice inoculated in the footpad, and spirochete burdens were dramatically reduced in mice inoculated in the dorsal lumbar skin compared to thoracic skin.” Further, dissemination of Bb happens in more ways than via blood and that these other ways, such as through the lymphatic system, may contribute to increased early colonization of the dura mater in mice. This was only true for early infection and by 28 days, Bb in the dura mater were comparable regardless of the inoculation site.
This article reveals what patients have been experiencing for decades: heads that feel as if they were going to explode. I wondered if there would ever be a day without a headache. I personally found that Minocycline was one of the most productive antibiotics for this.