MODELS OF P CARINII INFECTION: SP-A AND SP-D NULL MICE

P CARINII 感染模型：SP-A 和 SP-D 无效小鼠

• 批准号: 6390654
• 负责人: MICHAEL FRANCIS BEERS
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390654
• 关键词: Pneumocystis carinii; Pneumocystis pneumonia; alveolar macrophages; collagen; cytokine; disease /disorder model; gene targeting; genetic models; histopathology; host organism interaction; immunity; immunocytochemistry; laboratory mouse; lectin; lung alveolus; lung lavage; model design /development; pulmonary surfactants; surface property

Despite advances in diagnosis, therapy, and prophylaxis, Pneumocystis carinii pneumonia (PCP) remains a leading cause of morbidity and mortality in patients with HIV infection. The disease is caused by an enigmatic pathogen whose basic biology remains poorly understood because of difficulty in culturing the organism in vitro. Thus, animal models remain a mainstay of investigation into the pathogenesis of PCP. Although progress has been made in the definition of protective immunity in the immediate response to P carinii infection, an extremely important gap remains related to studies of the pathogenesis of this infection which centers around an inability to quantify various steps in pathogenesis in vivo. Surfactant protein A (SP-A) and surfactant protein D (SP-D) are collagen like lectins (collectins) which are highly expressed in the distal airways and alveolus. Both proteins have been shown to bind to and mediate the attachment of P carinii to the alveolar macrophage and to modulate cytokine elaboration by T-cell populations. Recent development of both SP-A and SP-D knockout mice has begun to implicate important roles for these proteins in local lung host defense and in modulation of the pulmonary inflammatory response. We hypothesize that SP-A and SP-D: a) Augment clearance of P. carinii from the alveolar space; b) Moderate a balance between pro- and anti-inflammatory responses which occurs during PCP. We propose to utilize the recently developed SP-A and SP-D knockout mice as new models of P. carinii infection to define the role of the collectins in host defense against PCP. The specific aims are: 1) Using SP-A and SP-D knockout mice, determine the role of the lung collectins (SP-A, SP-D) in the establishment and clearance of P. carinii infection in vivo; 2) Characterize the host immune response to P. carinii in SP-A and SP-D deficient models.; 3) Characterize changes in surfactant composition and function during development and progression of PC pneumonia in surfactant protein knockout mice; 4) Determine the effect of exogenous replacement of SP-A and/or SP-D on the clearance of P. carinii infection. The project will combine elements of several established thematic research programs to yield a comprehensive investigative proposal including: 1) A Principal Investigator with expertise in all major aspects of surfactant biology 2) Consultants recognized as authorities on immunocompromised mouse models of PCP and in generation of surfactant protein knockout mice. Results from these studies will extend our understanding of the pathogenesis of P. carinii infection.

尽管在诊断、治疗和预防方面取得了进展，卡氏肺囊虫肺炎（PCP）仍然是艾滋病毒感染患者发病和死亡的主要原因。这种疾病是由一种神秘的病原体引起的，由于很难在体外培养这种病原体，人们对其基本生物学仍然知之甚少。因此，动物模型仍然是研究PCP发病机制的主要手段。尽管在对卡氏杆菌感染的即时反应中的保护性免疫的定义方面取得了进展，但在卡氏杆菌感染发病机制的研究方面仍然存在一个极其重要的空白，这一空白主要集中在无法量化体内发病机制的各个步骤。表面活性剂蛋白A （SP-A）和表面活性剂蛋白D （SP-D）是胶原样凝集素（集合素），在远端气道和肺泡中高度表达。这两种蛋白已被证明结合并介导卡氏P对肺泡巨噬细胞的附着，并调节t细胞群的细胞因子加工。SP-A和SP-D基因敲除小鼠的最新进展已经开始暗示这些蛋白在局部肺宿主防御和肺部炎症反应调节中的重要作用。我们假设SP-A和SP-D: a)增加卡氏假单胞菌对肺泡间隙的清除；b)调节PCP期间发生的促炎和抗炎反应之间的平衡。我们建议利用最近开发的SP-A和SP-D敲除小鼠作为卡氏疟原虫感染的新模型，以确定收集物在宿主防御PCP中的作用。具体目的是：1)利用SP-A和SP-D敲除小鼠，确定肺收集物（SP-A、SP-D）在体内卡氏疟原虫感染的建立和清除中的作用；2)在SP-A和SP-D缺陷模型中表征宿主对卡氏假单胞菌的免疫反应；3)表征表面活性剂蛋白敲除小鼠PC肺炎发生发展过程中表面活性剂组成和功能的变化；4)确定外源性SP-A和/或SP-D替代对卡氏假单胞菌感染清除的影响。该项目将结合几个已建立的专题研究项目的要素，以产生一个全面的调查建议，包括：1)一位在表面活性剂生物学所有主要方面都具有专业知识的首席研究员；2)在PCP免疫受损小鼠模型和表面活性剂蛋白敲除小鼠的产生方面被公认为权威的顾问。这些研究结果将扩展我们对卡氏假杆菌感染发病机制的认识。