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

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-?B 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. Overall design: 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 using the Illumina HiSeq 4000.