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: 6653150
• 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 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6653150
• 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.

尽管诊断、治疗和预防方面取得了进展，卡氏肺孢子虫肺炎 (PCP) 仍然是 HIV 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，由于难以在体外培养这种生物体，人们对其基本生物学知之甚少。 因此，动物模型仍然是研究 PCP 发病机制的支柱。 尽管在对卡氏疟原虫感染立即反应的保护性免疫的定义方面已经取得了进展，但对该感染发病机制的研究仍然存在极其重要的差距，其中心是无法量化体内发病机制的各个步骤。 表面活性蛋白 A (SP-A) 和表面活性蛋白 D (SP-D) 是胶原蛋白样凝集素（集合素），在远端气道和肺泡中高度表达。 这两种蛋白均已被证明能够结合并介导卡氏疟原虫与肺泡巨噬细胞的附着，并调节 T 细胞群产生的细胞因子。 SP-A 和 SP-D 敲除小鼠的最新发展已开始表明这些蛋白质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 P. carinii 从肺泡腔的清除； b) 调节 PCP 期间发生的促炎反应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来确定集合素在宿主防御 PCP 中的作用。 具体目标是： 1）利用SP-A和SP-D敲除小鼠，确定肺集合素（SP-A、SP-D）在卡氏疟原虫体内感染建立和清除中的作用； 2) 表征 SP-A 和 SP-D 缺陷模型中对卡氏疟原虫的宿主免疫反应。 3）表征表面活性剂蛋白敲除小鼠PC肺炎发生和进展过程中表面活性剂组成和功能的变化； 4)确定外源性替代SP-A和/或SP-D对清除卡氏疟原虫感染的影响。 该项目将结合几个已建立的主题研究项目的要素，产生一个全面的研究建议，包括：1）在表面活性剂生物学所有主要方面拥有专业知识的首席研究员2）被公认为PCP免疫受损小鼠模型和表面活性剂蛋白敲除小鼠生成方面权威的顾问。 这些研究的结果将加深我们对卡氏疟原虫感染发病机制的理解。