Inflammatory mediators and mechanisms during central nervous system infection

描述（由申请方提供）：炎症是中枢神经系统（CNS）感染期间脑损伤的基本原因，也是在感染（如脑膜炎）期间沿着抗生素使用抗炎治疗的原因。皮质类固醇是目前唯一批准用于CNS细菌感染的抗炎治疗。然而，皮质类固醇是次优的，因为它们的益处仅限于高收入国家的个体，某些细菌的感染，最终不会改善长期的神经系统结果。因此，需要新的治疗方法来改善炎症病理学并提供更积极的患者结果。microRNA（miR）是在骨髓细胞中表达的短的非编码RNA，其作为先天性和适应性免疫应答的调节剂具有关键作用。我们的数据表明，在细菌性脑膜炎患者的脑脊液（CSF）以及感染嗜神经细菌L.单核细胞增多症（Lm）。miR-155上调与促炎细胞因子的上调和炎性白细胞向脑中的募集一致。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-6Chigh单核细胞和中性粒细胞，这表明miR-155限制了感染期间的炎症。 该提案的目标是建立新的发现，即miR-155在感染期间减少脑炎症中发挥作用，并确定miR-155在感染中的作用。 在脑膜炎患者和实验性小鼠感染中均发现感染诱导miR脑表达的机制。该提案的具体目标包括：目标1。阐明导致Lm感染期间miR-155-/-小鼠脑中炎性细胞流入增加的机制。我们的工作假设是，在CNS感染期间，miR-155的缺失导致脑中单核细胞和嗜中性粒细胞吸引趋化因子的产生增加。目标二。确定CNS感染期间上调脑中miR表达的关键生物刺激物。我们的工作假设是，最初的miR在大脑中的上调是由Lm感染期间产生的细胞因子驱动的。实验将部分使用Lm感染的小鼠模型以及包括骨髓嵌合体和器官型脑切片培养的新技术进行。这些目标的成功完成将首次确定特定miR在细菌感染期间影响脑炎症，并将评估靶向miR或表达特定miR的炎性细胞作为CNS感染的新型预防性治疗的潜在益处。这是发现调节CNS炎症的新分子靶点的必要的第一步。

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.