Role of T cells during central nervous system (CNS) bacterial infection

描述（由申请人提供）：脑脓肿的形成是化脓性细菌感染的结果，可引起炎症、水肿、神经元毒性，通常还可引起长期健康问题，如癫痫发作。脑脓肿的诊断和治疗是复杂的，未经治疗的病灶可能破裂进入脑室，这导致80%的死亡率。尽管进行了治疗，但脑脓肿的发生率可能会持续，这是由于细菌的普遍存在的性质和不断增加的多药耐药细菌菌株的数量，例如金黄色葡萄球菌（S。 aureus)具有良好的抗菌活性。拟议的培训计划与NINDS的使命相关，因为其广泛目标是减轻细菌性脑脓肿带来的神经疾病负担。在脑脓肿发生发展过程中，S.金黄色葡萄球菌的定义相对明确;然而，关于感染期间获得性免疫的重要性，几乎没有可用的信息。初步研究表明，脑脓肿中存在CD 4+、CD 8+、34 T细胞和NKT细胞浸润，提示需要先天性和适应性免疫应答来解决CNS中的细菌感染。基于浸润携带12 T细胞受体（TCR）的脑脓肿的T细胞群的频率，在缺乏CD 4+、CD 8+和NKT细胞的TCR 12 KO小鼠中进行了后续研究。与能够有效清除沙门氏菌的WT动物相比，TCR 12 KO小鼠在感染后期的细菌负荷显著增加。金黄色的TCR 12+细胞的损失也影响了浸润到CNS中的先天免疫细胞的分布，主要是在感染的晚期（即细菌暴露后的7-14天）。发现浸润脑的主要细胞类型CD 4+和NKT细胞产生IL-17和IFN-3，其参与先天免疫细胞的活化和细菌清除。该提议的假设是，CD 4 + Th 1/Th 17细胞和NKT细胞影响先天性免疫群体的流入和激活状态，以调节脑脓肿发生期间的细菌清除和组织损伤。为了评估Th 1和Th 17细胞在脑脓肿发病机制中的功能作用，研究计划将在特异性CD 4 + T辅助（Th）细胞群过继性转移到TCR 12 KO小鼠中后检查感染参数（即细菌负荷、促炎性介质表达、先天性免疫浸润和组织损伤）。此外，将使用缺乏NKT细胞的市售CD 1d缺陷小鼠评价感染期间NKT细胞的重要性。这些研究的目的是明确Th 1/Th 17和NKT细胞在脑脓肿发病机制中的功能作用，并首次建立脓肿形成过程中先天性免疫和获得性免疫之间的直接联系。可以预见，这些研究可以确定新的治疗靶点，以限制伴随脑脓肿的过度神经元损伤，并具有不损害有效细菌清除的额外益处。 公共卫生相关性：脑脓肿是一种毁灭性的感染，特别是由于最近出现的多药耐药细菌菌株，并可导致长期的缺陷，包括癫痫发作和认知丧失。在这个提议中，我将评估各种T细胞亚群在脑脓肿发展过程中影响抗细菌免疫的功能重要性。对T细胞应答如何调节炎症的更好理解可能揭示新的治疗靶点，以限制脑脓肿伴随的过度神经元损伤，并具有不损害有效细菌清除的额外益处。

DESCRIPTION (provided by applicant): Brain abscess formation is consequent of pyogenic bacterial infection, and can elicit inflammation, edema, neuronal toxicity, and often long-term health problems such as seizures. Diagnosing and treating brain abscesses is complicated, and untreated lesions can rupture into the ventricular space which engenders an 80% mortality rate. The incidence of brain abscesses is likely to persist, in spite of therapy, due to the ubiquitous nature of bacteria and the ever increasing number of multi-drug resistant bacterial strains such as Staphylococcus aureus (S. aureus). The proposed training plan is relevant to the mission of NINDS in that its broad objective is to reduce the burden of neurological disease brought on by bacterial-induced brain abscesses. The innate immune responses elicited during brain abscess development due to S. aureus are relatively well-defined; however, little information is available regarding the importance of adaptive immunity during infection. Preliminary studies have demonstrated CD4+, CD8+, 34 T cell, and NKT cell infiltrates in brain abscesses, suggesting both innate and adaptive immune responses are required to resolve bacterial infections in the CNS. Based on the frequency of T cell populations infiltrating brain abscesses bearing the 12 T cell receptor (TCR), subsequent studies were performed in TCR 12 KO mice, deficient in CD4+, CD8+, and NKT cells. Bacterial burdens were significantly elevated in TCR 12 KO mice at later stages of infection compared to WT animals, which were able to effectively clear S. aureus. The loss of TCR 12+ cells also affected the profiles of infiltrating innate immune cells into the CNS, primarily during the late phase of infection (i.e. days 7-14 following bacterial exposure). The predominant cell types infiltrating the brain, CD4+ and NKT cells, were found to produce IL-17 and IFN-3, which are involved in the activation of innate immune cells and bacterial clearance. The hypothesis of this proposal is that CD4+ Th1/Th17 cells and NKT cells impact the influx and activation status of innate immune populations to regulate bacterial clearance and tissue injury during brain abscess development. To assess the functional effects of Th1 and Th17 cells in brain abscess pathogenesis, the research plan will examine parameters of infection (i.e. bacterial burdens, pro-inflammatory mediator expression, innate immune infiltrates, and tissue injury) after specific CD4+ T helper (Th) cell populations are adoptively transferred into TCR 12 KO mice. In addition, the importance of NKT cells during infection will be evaluated using commercially available CD1d-deficient mice that lack NKT cells. The objective of these studies is to define the functional contributions of Th1/Th17 and NKT cells in brain abscess pathogenesis and establish for the first time a direct link between innate and adaptive immunity during abscess formation. It is envisioned that these studies may identify novel therapeutic targets to limit the excessive neuronal damage that accompanies brain abscesses with the added benefit of not compromising effective bacterial clearance. PUBLIC HEALTH RELEVANCE: Brain abscesses represent a devastating infection, especially due the recent emergence of multi-drug resistant strains of bacteria, and can cause long-term deficits including seizures and cognitive loss. In this proposal, I will assess the functional importance of various T cell subsets for their ability to influence anti-bacterial immunity during brain abscess development. A better understanding of how T cell responses regulate inflammation may reveal novel therapeutic targets to limit the excessive neuronal damage that accompanies brain abscesses with the added benefit of not compromising effective bacterial clearance.