Dectin-1 and Immunity Against Pneumocystis Carinii

描述（由申请人提供）：卡氏肺囊虫是免疫功能低下个体肺炎的重要原因，从肺环境中清除卡氏肺囊虫是肺泡巨噬细胞的专属责任。然而，由于卡氏假单胞菌无法在体外稳定培养，迄今为止，还没有高通量的活力测定来阐明先天细胞介导的宿主防御卡氏假单胞菌的机制。利用一种新的体外杀伤实验，我们发现肺泡巨噬细胞通过一种新描述的真菌β -葡聚糖受体Dectin-1识别和随后的非胞外杀伤P. carinii。Dectin-1是一种28 kDa的II型跨膜受体，包含一个单一的凝集素样碳水化合物识别结构域，该结构域可识别1,3-链和1,6-链葡聚糖。我们还观察到肺泡巨噬细胞对卡氏假单胞菌的炎症反应是由Dectin-1识别介导的。我们进一步表明，未成熟的肺源性树突状细胞表达高水平的Dectin-1。基于这些研究，我们假设decatin -1是针对卡氏假弧菌的非声速肺泡巨噬细胞效应功能以及树突状细胞介导的适应性T细胞应答激活所必需的。我们将用以下具体目标来检验这一假设。特异性目的1：在体外验证Dectin-1介导的卡氏疟原虫识别对肺泡巨噬细胞宿主防御卡氏疟原虫至关重要。具体目的2：验证卡氏假单胞菌诱导的肺部炎症需要β -葡聚糖识别的概念。特异性目的3：验证阻断Dectin-1介导的卡氏假体识别增加卡氏假体肺部感染易感性的概念。这些研究将研究一种新的真菌分子识别受体，并表征其在体外和体内对抗机会性真菌卡氏假单胞菌的作用，并可能为卡氏假单胞菌如何被免疫系统识别提供新的见解，从而可能导致新的免疫治疗策略来对抗这种毁灭性的肺部感染。

DESCRIPTION (provided by applicant): Elimination of Pneumocystis carinii, a significant cause of pneumonia in immunocompromised individuals, from the pulmonary environment is the exclusive responsibility of the alveolar macrophage. However, due to P. carinii's inability to be stably cultured in vitro, to date, there has been no high-throughput assay of viability to elucidate innate cell-mediated host defense mechanisms against P. carinii. Using a novel in vitro killing assay, we discovered that recognition and subsequent non-opsonic killing of P. carinii by alveolar macrophages occurs via a newly described receptor for fungal beta-glucans, Dectin-1. Dectin-1 is a 28 kDa, type II transmembrane receptor that contains a single lectin-like carbohydrate recognition domain which recognizes beta 1,3-linked and beta 1,6-linked glucans. We also observed that the alveolar macrophage inflammatory response to P. carinii is mediated by Dectin-1 recognition. We further show that immature lung-derived dendritic cells express high levels of Dectin-1. Based on these studies, we hypothesize that Dectin-1 is required for non-opsonic alveolar macrophage effector function against P. carinii as well as dendritic cell-mediated activation of adaptive T cell responses against P. carinii. We will test this hypothesis with the following specific aims. Specific Aim 1: To test the concept that Dectin-1 mediated recognition of P. carinii is critical for alveolar macrophage host defense against P. carinii in vitro. Specific Aim 2: To test the concept that beta-glucan recognition is required for P. carinii-induced pulmonary inflammation. Specific Aim 3: To test the concept that interruption of Dectin-1 mediated P. carinii recognition increases susceptibility to lung infection with P. carinii. These studies will investigate a new fungal molecular recognition receptor and characterize its role, in vitro as well as in vivo, against the opportunistic fungal organism P. carinii and may provide new insight into how P. carinii is recognized by the immune system, which may lead to novel immunotherapeutic strategies to combat this devastating pulmonary infection.