Models of P Carinii Infection: SP-A and SP-D Null Mice

描述（由申请人提供）：尽管在诊断、高效抗逆转录病毒治疗和预防方案方面取得了进展，但卡氏肺囊虫肺炎（PCP）仍然是HIV感染者发病率和死亡率的重要原因，也是其他免疫功能低下患者中一种重要的危及生命的机会性感染。肺囊虫进入肺远端触发适应性（细胞和体液）和先天免疫系统参与特异性炎症级联反应，其特征是CD4/CD8淋巴细胞反应的启动，促炎细胞因子的产生，单核细胞的募集，巨噬细胞的激活以及一氧化氮及其中间体的精细化。从肺灌洗液中分离的两种蛋白，表面活性剂蛋白(SP) -A和SP- d，是集合（胶原样凝集素）家族的成员，是局部非抗体介导的先天免疫反应的元件。在之前的资助期内，该项目在免疫功能低下的PCP小鼠模型中描述了PCP影响收集表达的作用和机制。在SP-A和SP-D缺失小鼠中，PCP与机体负荷增加和肺损伤有关。基于先前的结果，当前建议的总体主题是使用额外的新型小鼠收集表达模型和体外系统来定义这些局部先天宿主防御分子，肺囊虫，先天和适应性效应细胞以及远端肺上皮之间的相互作用。具体来说，我们建议：1)使用组成型过表达和诱导小鼠模型确定肺收集物（SP-A, SP-D）在清除肺囊虫感染和调节炎症相关肺损伤中的作用；2)在这些收集表达的小鼠模型中，明确免疫重建条件下PCP炎症相关表面活性物质功能障碍和肺损伤的细胞群和机制；3)表征收集物对PCP关键效应细胞反应的直接影响；4)从机制上明确收集物与一氧化氮代谢在PCP患者肺损伤调节中的关系。这些研究的结果对于加强我们对PCP发病机制的理解具有重要意义，因为流行病学研究将收集性遗传多态性与肺部疾病联系起来，并且最近报道了PCP治疗后免疫重建治疗后出现急性呼吸衰竭的患者。

DESCRIPTION (provided by applicant): Despite advances in diagnosis, highly active antiretroviral therapy, and prophylactic regimens, Pneumocystis carinii pneumonia (PCP) remains a significant cause of morbidity and mortality in HIV infected patients, as well as an important life-threatening opportunistic infection in other immunocompromised patients. Pneumocystis entry into the distal lung triggers involvement of both adaptive (cellular and humoral) and innate immune systems with specific inflammatory cascades characterized by initiation of CD4/CD8 lymphocyte responses, production of proinflammatory cytokines, recruitment of mononuclear cells, macrophage activation, and elaboration of nitric oxide and its intermediates. Two proteins isolated from lung lavage, surfactant protein (SP) -A and SP-D, members of the collectin (collagen-like lectin) family are elements of the local non-antibody mediated innate immune response. In the previous funding period, this project characterized the effects of and mechanisms by which PCP affected collectin expression in an immunocompromised mouse model of PCP. In both SP-A and SP-D null mice, PCP was associated with increased organism burden and lung injury. Building upon the previous results, the overall theme of the current proposal is to use additional novel murine models of collectin expression and in vitro systems to define the interplay between these local innate host defense molecules, Pneumocystis, innate and adaptive effector cells, and the distal pulmonary epithelia. Specifically we propose to: 1) Define the role of lung collectins (SP-A, SP-D) in clearance of Pneumocystis infection and modulation of inflammation-associated pulmonary injury using constitutively overexpressing and inducible mouse models; 2) Define cell populations and mechanisms contributing to inflammation associated surfactant dysfunction and lung injury in PCP under conditions of immune reconstitution in these murine models of collectin expression; 3) Characterize the direct effects of collectins on key effector cell responses in PCP; 4) Mechanistically define the relationship between the collectins and nitric oxide metabolism in modulating lung damage in PCP. Results from these studies are significant to enhancing our understanding of PCP pathogenesis in light of epidemiological studies linking collectin genetic polymorphisms with lung disease and recent reports of patients developing acute respiratory failure following immune reconstitution therapy after treatment for PCP.