PNEUMOCYSTIS CARINII PNEUMONIA MODEL

卡氏肺囊虫肺炎是免疫功能低下患者发病和死亡的主要原因，在获得性免疫缺陷综合征（艾滋病）患者中感染率特别高。由于缺乏连续的体外培养系统，卡氏肺囊虫肺炎（PCP）的病理生理学、宿主免疫反应和生物分子特征的研究依赖于动物模型。尽管这些动物模型有助于提供有关生物体性质和复杂的宿主-寄生虫相互作用的信息，但由于它们通常涉及广泛免疫抑制的动物，因此与人类PCP的相关性受到质疑。此外，已经积累了大量证据证明宿主物种特有的表型和基因型变异。由于这些原因，开发一种可复制的、模仿艾滋病的PCP的非人类灵长类动物模型，将为研究PCP的发病机制以及与人类最密切相关的宿主物种变异的分子方面提供若干优势。猴免疫缺陷病毒（SIV）感染的恒河猴会发生自发性PCP，初步证据表明，当外周血CD4+ T细胞计数低于总T细胞的约30%时，就会发生这种情况。由于个体宿主的可变性、环境因素和SIV感染过程的可变性，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功能低下、SIV感染的恒河猴中建立可重复的PCP感染，并利用该模型表征猴源卡氏疟原虫的表型和基因型变异。我们的假设是，这个模型将最接近于艾滋病的PCP，而在分子水平上，类人猿卡氏弓形虫将与人类卡氏弓形虫最接近。为了验证这些假设，我们建议通过在SIV感染的恒河猴中启动卡氏疟原虫感染来建立PCP模型。当SIV引起的外周血CD4+ T细胞下降达到外周血T细胞总数的30%时，猴子就会开始卡氏疟原虫感染。将监测疾病进展的各种表现，并恢复类人猿卡氏疟原虫的分子和抗原特征。这些研究将解决类人猿和人类卡氏弓形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的许多方面提供手段，这些方面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.