Protective Role of Interleukin 10 in Neuroborreliosis

描述（由申请人提供）：中枢神经系统（CNS）的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人类主要螺旋体感染包括梅毒、钩端螺旋体病、莱姆病和回归热(RF)。螺旋体感染中导致中枢神经系统侵袭和损伤的因素尚不清楚。我们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 螺旋体疏螺旋体的免疫活性小鼠会出现复发性螺旋体血症，伴有轻度脑膜炎和残留脑部感染，但没有脑损伤。在缺乏产生清除感染所需抗体的 B 细胞的情况下，小鼠会出现持续的高水平螺旋体血症、持续的中枢神经系统感染和广泛的小胶质细胞激活，而不会造成脑损伤。这些观察结果表明，在射频疏螺旋体病期间，大脑得到了很好的保护，免受损伤。最近发现，患有 RF 疏螺旋体病的人类和实验动物体内会产生大量细胞因子白细胞介素 10 (IL-10)，这表明 IL-10 在这种感染中发挥着重要的保护作用。外源重组 IL-10 可以减少感染疏螺旋体的 B 细胞缺陷小鼠的临床疾病和脑部炎症并降低病原体负荷，这一发现也支持了这一点。此外，B细胞缺陷小鼠中IL-10的缺乏会导致更高的病原体负荷、大脑和其他器官中更严重的微血管损伤以及因脑内/蛛网膜下腔出血而过早死亡。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 的脑微血管损伤要严重得多，与同基因血清型 1 相比，血清型 2 会导致更高的螺旋体血症和更多的全身性 IL-10 产生，从而导致比血清型 2 更高的中枢神经系统感染和更多的脑部 IL-10 产生。这表明 IL-10 在血脑屏障水平上具有重要的神经保护功能。可以利用 IL-10 在感染性或炎症性疾病期间保护血脑屏障这一发现具有潜在的临床意义。 R21 探索性应用的目标是研究 IL-10 对免疫功能正常小鼠患 RF 疏螺旋体病的保护作用。我们的主要假设是，全身和大脑中针对感染而产生的 IL-10 可以保护大脑，特别是大脑微循环免受损伤。该项目的具体假设是，IL-10 在螺旋体感染过程中对于保护血脑屏障的完整性和功能至关重要。我们建议通过以下 3 个具体目标来研究这一假设： 1- 研究免疫活性小鼠在急性和残留脑部感染 B. turicatae 期间产生的 IL-10。 2- 研究在 B. turicatae 感染期间 IL-10 缺乏对脑实质和脑血管的影响。 3-确定在B. turicatae感染期间IL-10是否保护血脑屏障的功能。公共卫生相关性：螺旋体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 对于保护脑血管免受感染期间的损伤可能非常重要。我们建议在螺旋体脑部感染的小鼠模型中研究这一点。

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.