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A Murine Model of Lyme Disease Demonstrates That Borrelia Species Colonize the Dura Mater and Induce Inflammation in the Central Nervous System.

ABSTRACT: Purpose: Studies on gene expression changes in joint and heart tissues of laboratory mice have provided insights into the localized host responses to Borrelia burgdorferi colonization; however, gene expression changes in the CNS of mice during B. burgdorferi infection remain unclear. Therefore, we took an unbiased approach to examine potential changes in the dura mater as well as the brain cortex and hippocampus at day 7 post-infection using RNA sequencing (RNA-seq). Methods: Dura mater, brain cortex, and hippocampal mRNA profiles of 6-8 week old C3H/HeN mice infected with B. burgdorferi strain 297 or mock infected (n=4 per group) were generated by paired-end sequencing using the Illumina HiSeq 4000. The sequence reads were aligned using STAR aligner followed by DESeq2 for differential expression analysis. qRT–PCR validation was performed using SYBR Green assays. Results: In the dura mater, the presence of B. burgdorferi is associated with upregulation of genes consistent with TLR/NF-κB signalling and associated inflammatory cytokines and chemokines in addition to upregulation of interferon stimulated genes. In contrast, the brain parenchyma exhibits mainly an increase in interferon stimulated genes in response to B. burgdorferi infection without an associated cytokine response. Conclusion: 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. Our results 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, as well as evaluating potential novel prophylactic and therapeutic interventions for this important disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE149287 | GEO | 2021/01/22

REPOSITORIES: GEO

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Project description:Patient-derived cells hold great promise for precision medicine approaches in human health. Fibroblast cells have been a major source of human cells for reprogramming and differentiating into specific cell types for disease modeling. Such cells can be isolated at various stages during life (presymptomatic, symptomatic, and advanced disease) and thus can potentially be used to model different phases of disease progression. In certain circumstances, however, tissues are not collected during life and only postmortem tissues are the only available source of fibroblasts. Fibroblasts cultured from postmortem human dura mater of individuals with neurodegenerative diseases have been suggested as a primary source of cells for in vitro modeling of neurodegenerative diseases. Although fibroblast-like cells from human and mouse dura mater have been previously described, their utility for reprogramming and direct differentiation protocols requires further characterization. In this study, cells derived from dermal biopsies of living subjects were compared to cells derived from postmortem dura mater. In two instances, we have isolated and compared dermal and dural cell lines from the same subject. Notably, such striking differences were observed between cells of dermal and dural origin that their fibroblast nature was brought into question. Compared to dermal fibroblasts, postmortem dura mater-derived cells demonstrated different morphology, slower growth rates, and a higher rate of karyotype abnormality. Dura mater-derived cells also failed to express fibroblast protein markers. When dermal fibroblasts and dural-derived cells from the same subject were compared, they exhibited significant differences in gene expression profiles. Ultimately, dura mater-derived cells were found to originate from a mixed mural lineage consisting of smooth muscle cells and pericytes. Our study argues for rigorous karyotyping of all postmortem derived cell lines and highlights significant limitations of postmortem human dura mater-derived cells for modeling normal biology or disease-associated pathobiology.

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A Murine Model of Lyme Disease Demonstrates That Borrelia Species Colonize the Dura Mater and Induce Inflammation in the Central Nervous System.

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