Casselli Timothy, Divan Ali, Vomhof-DeKrey Emilie E, Tourand Yvonne, Pecoraro Heidi L, Brissette Catherine A
Department of Biomedical Sciences, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota, United States of America.
Department of Surgery, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota, United States of America.
PLoS Pathog. 2021 Feb 1;17(2):e1009256. doi: 10.1371/journal.ppat.1009256. eCollection 2021 Feb.
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.
莱姆病由伯氏疏螺旋体及其相关菌种感染引起，可导致影响关节、心脏和包括中枢神经系统（CNS）在内的神经系统的炎症性病变。近交系实验小鼠已被用于确定伯氏疏螺旋体感染的动力学以及关节和心脏中的宿主免疫反应，然而在这些动物的中枢神经系统中缺乏类似的研究。用于研究中枢神经系统中宿主与伯氏疏螺旋体相互作用的易处理动物模型是理解中枢神经系统发病机制的关键。因此，我们对小鼠在早期和亚急性感染期间中枢神经系统中伯氏疏螺旋体定植的动力学及相关免疫反应进行了表征。通过荧光免疫组织化学、活体显微镜检查、细菌培养和定量PCR，我们发现伯氏疏螺旋体经常定植于C3H小鼠的硬脑膜，感染后第7天螺旋体负荷达到峰值。观察到几种莱姆病病原体包括伯氏疏螺旋体、伽氏疏螺旋体和马氏疏螺旋体均可定植于硬脑膜。RNA测序和定量RT-PCR显示，伯氏疏螺旋体感染与硬脑膜中炎性细胞因子表达增加和强烈的干扰素（IFN）反应相关。在受感染动物的脑膜中也观察到包括白细胞浸润和血管变化在内的组织病理学变化。与脑膜相反，我们在感染期间未在大脑皮层或海马体中检测到伯氏疏螺旋体、浸润的白细胞或细胞因子谱的大规模变化；然而，这两个脑区在干扰素刺激基因表达方面表现出与外周组织和脑膜中观察到的类似变化。综上所述，伯氏疏螺旋体能够在实验小鼠的脑膜中定植，并诱导类似于外周组织的局部炎症。在没有伯氏疏螺旋体或炎性细胞因子的情况下，大脑实质中出现的无菌性干扰素反应是其独特之处，这为深入了解与这种重要病原体相关的中枢神经系统病理学潜在机制提供了线索。
