Inflammatory mediators and mechanisms during central nervous system infection

描述（由申请人提供）：炎症是中枢神经系统（CNS）感染期间脑损伤的基本原因，也是在脑膜炎等感染期间抗炎治疗与抗生素一起使用的原因。皮质类固醇是目前唯一被批准用于治疗中枢神经系统细菌感染的抗炎药物。然而，皮质类固醇并不是最理想的，因为它们的益处仅限于高收入国家的个人，仅限于某些细菌感染，最终不能改善长期的神经系统预后。因此，需要新的治疗方法来改善炎症病理并提供更积极的患者结果。MicroRNA （miR）是一种短的非编码RNA，在髓细胞中表达，在先天和适应性免疫反应中起关键调节作用。我们的数据表明，几种miR，如miR-155，在细菌性脑膜炎患者的脑脊液（CSF）中以及在嗜神经细菌单核增生乳杆菌（Lm）感染的小鼠的大脑中上调。miR-155的上调与促炎细胞因子的上调和炎性白细胞进入大脑的募集相一致。值得注意的是，本文提供的初步数据显示，miR-155-/-小鼠比正常小鼠向大脑募集更多的ly - 6high单核细胞和中性粒细胞，这表明miR-155在感染期间限制了炎症。本提案的目标是建立新的发现，即miR-155在减少感染期间的脑炎症中起作用，并确定miR-155在脑炎症中的作用

DESCRIPTION (provided by applicant): Inflammation is a foundational cause of brain injury during central nervous system (CNS) infections and the reason why anti-inflammatory therapy is used along with antibiotics during infections such as meningitis. Corticosteroids are the only anti-inflammatory treatment currently approved for bacterial infections of the CNS. However, corticosteroids are sub-optimal as their benefit is restricted to individuals in high-income countries, to infections with certain bacteria, and ultimately do not improve long-term neurological outcomes. Thus, new therapies are needed that will ameliorate inflammatory pathology and deliver more positive patient outcomes. MicroRNA (miR) are short, non-coding RNA expressed in myeloid cells that have key roles as modulators of innate and adaptive immune responses. Our data suggest several miR, e.g. miR-155, are up-regulated in cerebrospinal fluid (CSF) of patients with bacterial meningitis as well as in the brains of mice infected with the neurotropic bacterium, L. monocytogenes (Lm). miR-155 up-regulation coincides with up-regulation of pro-inflammatory cytokines and recruitment of inflammatory leukocytes into the brain. Notably, preliminary data presented here show miR-155-/- mice recruit more Ly-6Chigh monocytes and neutrophils to the brain than do normal mice suggesting miR-155 limits inflammation during infection. The goals of this proposal are to establish the novel finding that miR-155 has a role in reducing brain inflammation during infection and to identify the mechanisms by which infection induces brain expression of miR that are found both in patients with meningitis and in experimental mouse infection. Specific Aims of this proposal include: Aim 1. Elucidate the mechanisms leading to increased inflammatory cell influxes in the brains of miR-155-/- mice during Lm infection. Our working hypothesis is that loss of miR-155 leads to increased production of monocyte and neutrophil-attracting chemokines in the brain during CNS infection. Aim 2. To identify key biological stimuli that up-regulate miR expression in the brain during CNS infection. Our working hypothesis is that the initial miR up-regulation in the brain is driven by cytokines produced during Lm infection. Experiments will be performed in part using the mouse model of Lm infection as well as with novel techniques including bone marrow chimeras and organotypic brain slice cultures. Successful completion of these aims will establish for the first time that a specific miR influences brain inflammation during bacterial infection and will gauge the potential benefit of targeting miRs or specific miR-expressing inflammatory cells as novel adjunctive treatment for CNS infections. This is a necessary first step towards discovering new molecular targets for modulating CNS inflammation.