A murine model of Lyme disease demonstrates that Borrelia burgdorferi colonizes the dura mater and induces inflammation in the central nervous system.
A murine model of Lyme disease demonstrates that Borrelia burgdorferi colonizes the dura mater and induces inflammation in the central nervous system.
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莱姆病的鼠模型表明伯氏疏螺旋体定殖于硬脑膜并诱导中枢神经系统中的炎症。
DOI：
10.1371/journal.ppat.1009256
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Brissette CA
中科院分区：
文献类型：
--
作者：
Casselli T;Divan A;Vomhof-DeKrey EE;Tourand Y;Pecoraro HL;Brissette CA
莱姆病由伯氏疏螺旋体和相关物种感染引起，可导致影响关节、心脏和神经系统（包括中枢神经系统（CNS））的炎性病理。已使用近交实验室小鼠来确定B的动力学。然而，在这些动物的CNS中缺乏类似的研究。研究中枢神经系统中宿主-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，我们表征了B的动力学。在早期和亚急性感染期间，小鼠CNS中的伯氏菌定殖和相关的免疫应答。通过荧光免疫组织化学、活体显微镜、细菌培养和定量PCR，我们发现了B。伯氏螺旋体通常定殖于C3 H小鼠的硬脑膜，在感染后第7天达到螺旋体负荷的峰值。观察到几种莱姆病病原体（包括B）在硬脑膜定植。burgdorferi，B. garinii和B.蛋黄酱RNA测序和定量RT-PCR结果表明，B.在硬脑膜中，伯氏菌感染与炎性细胞因子的表达增加和强干扰素（IFN）应答相关。在感染动物的脑膜中也观察到组织学变化，包括白细胞浸润和血管变化。与脑膜相反，我们没有检测到B。感染期间，在大脑皮层或海马中的细胞因子谱中存在Burgdorferi、浸润性白细胞或大规模变化;然而，这两个脑区域表现出与在外周组织和脑膜中观察到的IFN刺激的基因的表达类似的变化。加在一起，B。Burgdorferi能够在实验室小鼠的脑膜中定殖，并诱导类似于外周组织的局部炎症。无B时的无菌IFN应答。Burgdorferi或炎性细胞因子是脑实质所特有的，并提供了对与该重要病原体相关的CNS病理学的潜在机制的深入了解。莱姆病是响应于伯氏疏螺旋体感染的炎症诱导的组织病理学的结果。在理解莱姆病的神经系统表现方面取得进展的一个主要障碍是缺乏一种易于处理的实验室动物模型来评估中枢神经系统发病机制。在这里，我们解决了这一障碍，首次表征的动力学伯氏疏螺旋体定植在脑膜的实验室小鼠，脑膜和大脑中产生的免疫反应。我们证明了感染小鼠脑膜中活螺旋体的存在和动力学，并表明脑膜感染是几种莱姆病疏螺旋体物种共有的普遍现象。脑膜定植与浸润性白细胞和免疫反应基因的局部变化有关，这些基因以前被证明与莱姆病病理学有关。有趣的是，我们发现免疫反应基因的表达增加，包括那些参与大脑中抗原呈递的基因，尽管在该组织中缺乏可检测到的浸润性细菌或白细胞。总的来说，这些研究结果表征了中枢神经系统对伯氏疏螺旋体感染的反应，在一个具有成本效益和遗传稳健的动物模型，并提供了与莱姆病相关的神经病理机制的见解。
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. 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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DOI：
10.4269/ajtmh.1992.47.605
发表时间：
1992-11-01
影响因子：
3.3
作者：
BARTHOLD, SW;SIDMAN, CL;SMITH, AL
通讯作者：
SMITH, AL
影响因子：
3.1
作者：
Behera, AK;Hildebrand, E;Hu, LT
通讯作者：
Hu, LT
影响因子：
3.7
作者：
Casselli, Timothy;Qureshi, Humaira;Brissette, Catherine A.
通讯作者：
Brissette, Catherine A.
影响因子：
3.1
作者：
Brown, CR;Reiner, SL
通讯作者：
Reiner, SL
影响因子：
3.7
作者：
BLUTHE, RM;PAWLOWSKI, M;DANTZER, R
通讯作者：
DANTZER, R