HOST DEFENSE AGAINST INTRACELLULAR INFECTION OF THE LUNG

描述(改编自申请人的摘要)：细胞内 嗜肺军团菌等病原体被从肺中清除 未知。肺泡巨噬细胞寄生的机制 (AM)，细胞因子之间的相互作用介导免疫调节和 AM的效应细胞功能及其相对贡献 巨噬细胞活化和细胞毒反应 肺部的细胞内感染尚不清楚。不断增长的人口 易受机会性感染的免疫功能受损的个体 强调制定新战略的重要性， 预防和治疗细胞内感染。最新进展 有效的疫苗和免疫疗法取决于对 保护性宿主的反应。这样做的长期目标是 建议是定义分子和细胞成分的保护性 宿主对肺部细胞内感染的反应和识别 通过组合提高寄主抗性的潜在途径 与人AM的体外工作和对小鼠的体内研究 细胞因子缺乏。拟议的研究基于以下几点 假设：1)嗜肺性乳杆菌在人AM中的存活受 通过刺激或抑制细胞的细胞因子的平衡 通过调节细菌摄取和细胞因子来抵抗感染 细胞内铁的利用率。有毒的有机体操纵 细胞因子的反应有利于它们在细胞内存活。2)首字母 嗜肺乳杆菌与人AM的相互作用是由模式介导的 识别受体，如CD14，介导细菌结合和 嗜肺乳杆菌、脂多糖和全菌对细胞因子的反应。3)INF- 细胞内拆分需要伽马和肿瘤坏死因子-α 肺感染，作为AM和AM激活的基本信号 自然杀伤(NK)细胞对感染细胞的破坏和 细胞毒性淋巴细胞(CTL)。具体目标是：1)界定 允许或保护的细胞因子图谱 嗜肺乳杆菌对人AM细胞内感染的研究 有毒生物是否操纵AM的反应以有利于它们的 细胞内存活：2)确定模式识别 CD14等受体介导细菌结合和细胞因子 人AM对嗜肺乳杆菌脂多糖和全菌的反应； 勾勒出巨噬细胞活化和活化的相对贡献 细胞毒反应在肺炎军团菌病治疗中的作用 转基因小鼠的比较研究和选择性重组 缺乏干扰素-γ或肿瘤坏死因子-α。

DESCRIPTION (Adapted from the applicant's abstract): How intracellular pathogens such as Legionella pneumophila are eliminated from the lung is unknown. The mechanisms underlying parasitism of alveolar macrophages (AM), the interactions of cytokines mediating the immunoregulatory and effector cell functions of AM, and the relative contributions of macrophage activation and cytotoxic responses to the resolution of intracellular infection in the lung are unknown. The growing population of immunocompromised individuals susceptible to opportunistic infection underscores the importance of developing new strategies for the prevention and treatment of intracellular infections. The development of effective vaccines and immunotherapy is dependent on an understanding of the protective host response. The long-term objective of this proposal is to define molecular and cellular elements of the protective host responses to intracellular infections of the lung and to identify potential approaches to the augmentation of host resistance by combining in vitro work with human AM and in vivo studies in mice with specific cytokine deficiencies. The proposed studies are based on the following hypotheses: 1) The survival of L. pneumophila in human AM is governed by the balance of cytokines that stimulate or inhibit cellular resistance to infection by regulating bacterial uptake and the availability of intracellular iron. Virulent organisms manipulate the cytokine response to favor their intracellular survival. 2) The initial interaction of human AM with L. pneumophila is mediated by pattern recognition receptors such as CD14, that mediate bacterial binding and the cytokine response to L. pneumophila LPS and whole bacteria. 3) INF- gamma and TNF-alpha are required for the resolution of intracellular infection of the lung, as essential signals for the activation of AM and the destruction of infected cells by natural killer (NK) cells and cytotoxic lymphocytes (CTL). The specific aims are: 1) to define cytokine profiles that are permissive of or protective against intracellular infection of human AM by L. pneumophila, and establish whether virulent organisms manipulate the responses of AM to favor their intracellular survival: 2) to determine whether pattern recognition receptors such as CD14 mediate bacterial binding and the cytokine response of human AM to L. pneumophila LPS and whole bacteria; and 3) to delineate the relative contribution of macrophage activation and cytotoxic responses in the resolution of pneumonic legionellosis through the comparative study and selective reconstitution of transgenic mice deficient in INF-gamma or TNF-alpha.