HOST DEFENSE AGAINST INTRACELLULAR INFECTION OF THE LUNG

描述（改编自申请人摘要）：细胞内如何 病原体如嗜肺军团菌从肺中消除， 未知 肺泡巨噬细胞的寄生机制 (AM)，介导免疫调节的细胞因子的相互作用， AM的效应细胞功能，以及 巨噬细胞活化和细胞毒反应的决议， 肺内的细胞内感染是未知的。 不断增长的人口 免疫功能低下的个体容易受到机会性感染 强调必须制定新的战略， 预防和治疗细胞内感染。 发展 有效的疫苗和免疫疗法依赖于理解 宿主的保护性反应 长期目标是 建议是定义分子和细胞元件的保护 宿主对肺细胞内感染的反应， 通过组合提高寄主抗性的潜在途径 在体外对人AM进行研究和在小鼠中进行体内研究， 细胞因子缺乏 拟议的研究基于以下几点： 假设：1）L.人类AM中的嗜肺细胞 通过刺激或抑制细胞因子的平衡， 通过调节细菌的摄取来抵抗感染， 细胞内铁的可用性。 有毒的有机体操纵着 细胞因子应答以有利于它们的细胞内存活。 2)初始 人AM与L.嗜肺性肺炎是由模式介导的 识别受体，如CD 14，介导细菌结合， 细胞因子对L.嗜肺菌LPS和全菌。 3)INF- γ和TNF-α是解决细胞内 肺感染，作为激活AM的重要信号， 自然杀伤（NK）细胞对感染细胞的破坏， 细胞毒性淋巴细胞（CTL）。 具体目标是：（1）确定 细胞因子谱允许或保护 L. pneumophila，并建立 是否有毒生物操纵AM的反应，以有利于他们的 细胞内存活：2）确定模式识别是否 受体如CD 14介导细菌结合， 人AM对L.嗜肺菌LPS和全菌;和3） 描述巨噬细胞活化的相对贡献， 细胞毒性反应在肺军团菌病的解决， 转基因小鼠的比较研究和选择性重建 缺乏INF-γ或TNF-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.