Protective Role of Interleukin 10 in Neuroborreliosis

描述(由申请人提供)：中枢神经系统(CNS)的细菌感染是发病率和死亡率的重要原因。引起中枢神经系统感染和神经系统疾病的主要人类螺旋体感染包括梅毒、钩端螺旋体病、莱姆病和复发热(RF)。在螺旋体感染中，中枢神经系统的侵袭和损伤的因素还知之甚少。我们实验室一直在研究螺旋体中枢神经系统感染合并RF和莱姆病的发病机制，称为神经疏螺旋体病。免疫功能正常的小鼠经系统接种滴虫螺旋体后，出现复发性螺旋体血症，伴有轻度脑膜炎和残留的脑感染，但无脑损伤。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，以及广泛的小胶质细胞激活，而不会对大脑造成损伤。这些观察表明，在RF疏螺旋体病期间，大脑受到很好的保护，免受伤害。最近发现，人和实验动物在RF螺旋体病中产生了大量的细胞因子IL-10，这表明IL-10在这种感染中起着重要的保护作用。外源重组IL-10减少了感染疏螺旋体的B细胞缺陷小鼠的临床疾病和脑部炎症，并降低了病原体负荷，这一发现也支持这一点。此外，B细胞缺陷小鼠的IL-10缺乏会导致更高的病原菌负荷量和更严重的脑等器官微血管损伤，并导致脑内/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基因缺陷小鼠中，血清2型的脑微血管损伤更为严重，其引起的螺旋体血症和全身IL-10的产生高于同基因的1型，后者导致中枢感染和脑内IL-10的产生高于2型。这表明IL-10在血脑屏障水平上具有重要的神经保护作用。在感染性或炎症性疾病期间，人们可以利用IL-10保护血脑屏障，这一发现具有潜在的临床意义。本R21探索性应用的目的是研究IL-10在免疫活性小鼠RF螺旋体病中的保护作用。我们的主要假设是，在系统和大脑中对感染作出反应时产生的IL-10总体上保护大脑，特别是大脑微循环免受伤害。该项目的特定假设是，IL-10在螺旋体感染过程中是必不可少的，以保护血脑屏障的完整性和功能。我们建议研究这一假说有以下三个具体目的：1-研究免疫活性小鼠在急性和残留脑感染期间产生IL-10的情况。2-研究IL-10缺乏对脑实质和脑血管的影响。3-确定IL-10在感染斑疹杆菌期间是否保护血脑屏障的功能。公共卫生相关性：由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，白介素10可能在保护脑血管免受感染期间的损害方面起着非常重要的作用。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.