Structure and Expression of Pneumocystis Antigen Genes

描述（由申请人提供）：肺孢子虫肺炎是艾滋病患者和其他免疫功能低下个体的严重问题。这种疾病是由一种不寻常的真菌（肺孢子虫jirovecii）引起的，这种真菌在人体外很少增殖。因此，对肺孢子虫生物学的研究主要依赖于分别栖息于大鼠和小鼠的卡氏肺孢子虫和鼠肺孢子虫。在卡氏肺孢子虫和鼠肺孢子虫的研究中，人类肺孢子虫至少有一个基因家族（MSG）与抗原变异有关。在本申请中，我们提出了在啮齿动物肺孢子虫物种的基因家族（MSG，PRT，MSR）的结构和功能的研究。这些研究的总体目标是确定肺孢子虫基因家族的功能是否允许该属的成员寄生于免疫活性宿主。目的1将利用卡氏肺孢子虫的基因组数据来确定基因家族编码的蛋白质在哪里发生变化，以及这种变化是如何进化的。推导出进化的模式将使我们能够推断出一般的功能。目的2将使用基因组信息来研究卡氏肺孢子虫MSG家族的表达，这是一个需要在独特表达位点重组以引起表达基因序列变化的过程。大量的证据表明，基因转换在表达的MSG拷贝中产生了变异。目标2将研究这一点和其他可能性。目的3将确定在鼠肺吸虫DCS基因座发生重组的频率。这些研究将建立小鼠作为研究肺孢子虫抗原变异的模型，并为目标4所述的研究奠定基础，该研究将测试适应性免疫应答可以影响位于表达位点的MSG基因序列变异程度的想法。

DESCRIPTION (provided by applicant): Pneumocystis pneumonia is a serious problem for AIDS patients and other immunocompromised individuals. This illness is caused by an unusual fungus (Pneumocystis jirovecii) that proliferates little when outside of a human being. Therefore, studies on the biology of Pneumocystis have relied principally upon P. carinii and P. murina, which inhabit rats and mice, respectively. Human Pneumocystis has at least one gene family (MSG) that has been implicated in antigenic variation in studies on P. carinii and P. murina. In this application, we propose structural and functional studies on gene families (MSG, PRT, MSR) in rodent Pneumocystis species. The overall goal of these studies is to determine if Pneumocystis gene families function to allow members of this genus to parasitize an immunocompetent host. Aim 1 will employ genomic data from P. carinii to determine where the proteins encoded by a gene family vary, and how this variability evolved. Deducing the mode of evolution will allow us to infer general function. Aim 2 will use genomic information to investigate expression of the P. carinii MSG family, a process that entails recombination at a unique expression site to cause a change in the sequence of the expressed gene. The bulk of the evidence suggests that gene conversion creates variation in the expressed copy of MSG. Aim 2 will examine this and other possibilities. Aim 3 will determine how often recombination occurs at the DCS locus of P. murina. These studies will both establish mice as a model for studying antigen variation in Pneumocystis, and set the stage for studies described in Aim 4, which will test the idea that the adaptive immune response can influence the degree of variation in MSG gene sequences residing at the expression site.