PNEUMOCYSTIS CARINII PNEUMONIA MODEL

卡氏肺孢子虫肺炎是免疫功能低下患者发病和死亡的主要原因，尤其是获得性免疫缺陷综合征(AIDS)患者的感染率较高。由于缺乏连续的体外培养系统，对卡氏肺孢子虫肺炎(PCP)的病理生理、宿主免疫反应和生物体的分子特征的研究一直依赖于动物模型。虽然这些动物模型在提供有关生物体的性质和复杂的宿主-寄生虫相互作用的信息方面很有用，但由于它们通常涉及广泛的免疫抑制动物，因此与人类PCP的相关性一直受到质疑。此外，已有大量证据表明寄主物种特有的表型和基因变异。出于这些原因，开发一种可重现的、非人类的、模仿艾滋病疾病的PCP灵长类动物模型，将为研究PCP的发病机制以及在与人类关系最密切的模型中研究宿主物种变异的分子方面提供几个优势。感染猴免疫缺陷病毒(SIV)的恒河猴会发生自发性PCP，初步证据表明，当外周CD4+T细胞数量低于T细胞总数的30%时，就会发生这种情况。由于宿主个体的变异性、环境因素以及SIV感染过程中的变异性，SIV感染动物中PCP的发生是不可预测的。本研究的主要目的是在免疫受损、SIV感染的恒河猴中建立一种可复制的PCP感染模型，并使用该模型来表征猿源卡氏肺孢子虫的表型和基因变异。我们的假设是，这个模型将与艾滋病中的PCP最相似，而猿猴卡氏肺孢子虫将在分子水平上与人类卡氏肺孢子虫最接近。为了验证这些假设，我们建议通过在感染SIV的恒河猴中启动卡氏肺孢子虫感染来建立PCP模型。当SIV引起的外周血中CD4+T细胞下降达到外周血T细胞总数的30%时，猴子就会开始感染卡氏肺孢子虫。将监测疾病进展的各种表现，并将恢复卡氏狸殖吸虫进行分子和抗原性鉴定。这些研究将解决猿猴和人类卡氏肺吸虫之间的相似性问题，并确定非人类灵长类动物模型的相关性，从而为研究PCP的许多方面提供了手段，以前由于其他动物模型的限制而无法接近。

Pneumocystis carinii pneumonia is a primary cause of morbidity and mortality in immunocompromised patients, with particularly high infection rates in patients with acquired immunodeficiency syndrome (AIDS). Studies of the pathophysiology of Pneumocystis carinii pneumonia (PCP), host immune responses, and molecular characterizations of the organism have relied on animal models because of the lack of continuous in vitro culture systems. Although these animal models have been useful in producing information regarding the nature of the organism and the complex host-parasite interaction, the relevance to human PCP has been questioned since they generally involve broadly immunosuppressed animals. In addition, much evidence has been accumulated that demonstrates host species specific phenotypic and genotypic variation. For these reasons, the development of a reproducible, nonhuman primate model of PCP which mimics the disease seen in AIDS would provide several advantages for studying the pathogenesis of PCP and the molecular aspects of host species variations in a model most closely related to humans. Simian immunodeficiency virus (SIV) infected rhesus macaques develop spontaneous PCP, and preliminary evidence suggests that this occurs when peripheral CD4+ T cells counts falls below approximately 30 percent of the total T cells. The occurrence of PCP in SIV infected animals is not predictable due to individual host variability, environmental factors, and the variability in the course of the SIV infection. The primary goals of this study are to develop a reproducible PCP infection in immunocompromised, SIV infected rhesus macaques and to use this model to characterized the phenotypic and genotypic variation of simian derived P. carinii. It is our hypothesis that this model will most closely resemble PCP in AIDS and that the simian P. carinii will be most closely related to human P. carinii at the molecular level. To test these hypotheses, we propose to develop a PCP model by initiating a P. carinii infection in SIV infected rhesus macaques. The P. carinii infection will be initiated in monkeys when the SIV -induced decline in peripheral CD4+ T cells reaches 30 percent of the total peripheral blood T cells. Various manifestations of the disease progression will be monitored and simian P. carinii will be recovered for molecular and antigenic characterizations. These studies will address the question of similarities between simian and human P. carinii and determine the relevance of the nonhuman primate model, thus providing the means to study many aspects of PCP previously unapproachable due to the limitations of other animal models.