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Protective Role of Interleukin 10 in Neuroborreliosis

白细胞介素 10 在神经疏螺旋体病中的保护作用

基本信息

批准号：
7585262
负责人：
DIEGO CADAVID
金额：
$ 22.06万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2010-09-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Bacterial infections of the central nervous system (CNS) are an important cause of morbidity and mortality. The major spirochetal infections of humans causing CNS infection and neurological disease include syphilis, leptospirosis, Lyme disease and relapsing fever (RF). The factors responsible for CNS invasion and injury in spirochetal infections are poorly understood. Our laboratory has been studying the pathogenesis of spirochetal CNS infection with RF and Lyme disease, referred to as neuroborreliosis. Immunocompetent mice inoculated systemically with the RF spirochete Borrelia turicatae develop relapsing spirochetemia with mild meningitis and residual brain infection but without brain injury. In the absence of B cells that produce the antibodies needed to clear the infection, mice develop constant high level spirochetemia, persistent CNS infection, and widespread microglial activation without brain injury. These observations suggest that the brain is well protected from injury during RF borreliosis. The recent finding that large amounts of the cytokine Interleukin 10 (IL-10) are produced in humans and experimental animals with RF borreliosis suggests that IL- 10 plays an important protective role in this infection. The discovery that exogenous recombinant IL-10 reduces clinical disease and brain inflammation and lowers the pathogen load in B cell deficient mice infected with Borrelia turicatae also supports this. Furthermore, IL-10 deficiency in B cell deficient mice resulted in higher pathogen load and more severe microvascular injury in the brain and other organs and early death from intracerebral/subarachnoid hemorrhage. These results support a fundamental protective role for IL-10 in RF borreliosis. In IL-10 deficient mice brain microvascular injury was much more severe with serotype 2, which causes higher spirochetemia and more systemic production of IL-10 than isogenic serotype 1, which causes higher CNS infection and greater cerebral production of IL-10 than serotype 2. This suggests an important neuroprotective function of IL-10 at the level of the blood-brain barrier. The finding that one could utilize IL-10 to protect the blood brain barrier during infectious or inflammatory disorders is of potential clinical relevance. The goal of this R21 exploratory application is to study the protective role of IL-10 in RF borreliosis in immunocompetent mice. Our main assumption is that IL-10 produced in response to the infection both systemically and in the brain protects the brain in general, and the cerebral microcirculation in particular, from injury. The specific hypothesis for this project is that IL-10 is essential during spirochetal infection to protect the integrity and preserve the function of the blood brain barrier. We propose to study this hypothesis with the following 3 specific aims: 1- Study the production of IL-10 by immunocompetent mice during acute and residual brain infection with B. turicatae. 2- Investigate the consequences of IL-10 deficiency to the brain parenchyma and cerebral blood vessels during infection with B. turicatae. 3- Determine whether IL-10 protects the function of the blood-brain barrier during infection with B. turicatae. PUBLIC HEALTH RELEVANCE: Infection by a group of bacteria called spirochetes is an important cause of brain disease in humans. Our preliminary results indicate that Interleukin 10 may be very important to protect the brain blood vessels from damage during this infection. We propose to study this in a mouse model of spirochetal brain infection.

描述（由申请方提供）：中枢神经系统（CNS）细菌感染是发病和死亡的重要原因。引起中枢神经系统感染和神经系统疾病的主要螺旋体感染包括梅毒、钩端螺旋体病、莱姆病和回归热。对螺旋体感染中CNS侵袭和损伤的因素知之甚少。我们的实验室一直在研究螺旋体中枢神经系统感染RF和莱姆病，称为神经疏螺旋体病的发病机制。全身接种RF螺旋体的免疫活性小鼠发生复发性螺旋体血症，伴有轻度脑膜炎和残留脑感染，但无脑损伤。在缺乏产生清除感染所需的抗体的B细胞的情况下，小鼠发展出恒定的高水平螺旋体血症、持续的CNS感染和广泛的小胶质细胞活化，而没有脑损伤。这些观察结果表明，在RF疏螺旋体病期间，大脑受到很好的保护免受损伤。最近的发现，大量的细胞因子白细胞介素10（IL-10）产生的人类和实验动物与RF疏螺旋体病表明，IL- 10在这种感染中起着重要的保护作用。外源重组IL-10减少临床疾病和脑炎症并降低感染疏螺旋体的B细胞缺陷小鼠中的病原体负荷的发现也支持这一点。此外，在B细胞缺陷小鼠中，IL-10缺陷导致更高的病原体负荷和更严重的脑和其他器官中的微血管损伤以及脑内/蛛网膜下腔出血的早期死亡。这些结果支持IL-10在RF疏螺旋体病中的基本保护作用。在IL-10缺陷小鼠中，血清型2的脑微血管损伤严重得多，血清型2导致比同基因血清型1更高的螺旋体血症和更多的IL-10的全身产生，血清型1导致比血清型2更高的CNS感染和更多的IL-10的脑产生。这表明IL-10在血脑屏障水平具有重要的神经保护功能。在感染性或炎症性疾病期间可以利用IL-10来保护血脑屏障的发现具有潜在的临床意义。该R21探索性应用的目的是研究IL-10在免疫活性小鼠中RF疏螺旋体病中的保护作用。我们的主要假设是，IL-10在全身和大脑中响应感染而产生，一般保护大脑，特别是大脑微循环免受损伤。该项目的具体假设是，IL-10在螺旋体感染期间对于保护血脑屏障的完整性和功能至关重要。我们提出研究这一假设有以下3个具体目标：1-研究IL-10的生产免疫活性小鼠在急性和残留的脑感染与B。turiclavia。2-探讨B感染时IL-10缺乏对脑实质和脑血管的影响。turiclavia。3-确定IL-10是否在B感染期间保护血脑屏障的功能。turiclavia。公共卫生相关性：被一组称为螺旋体的细菌感染是人类脑部疾病的重要原因。我们的初步结果表明，白细胞介素10可能是非常重要的，以保护脑血管免受损害，在这种感染。我们建议在螺旋体脑感染的小鼠模型中研究这一点。