Structure and Expression of Pneumocystis Antigen Genes

描述（由申请人提供）：肺囊虫性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（氏肺囊虫）引起的，这种真菌在人体外增殖很少。因此，肺囊虫的生物学研究主要依赖于分别栖息在大鼠和小鼠体内的卡氏假体和鼠形假体。人类肺囊虫至少有一个基因家族（MSG）在卡氏假体和鼠形假体的研究中涉及抗原变异。在本应用程序中，我们提出了基因家族（MSG， PRT， MSR）在啮齿动物肺囊虫种的结构和功能的研究。这些研究的总体目标是确定肺囊虫基因家族的功能是否允许该属的成员寄生在具有免疫能力的宿主上。目的1将利用来自卡氏疟原虫的基因组数据来确定基因家族编码的蛋白质在何处发生变化，以及这种变异性是如何进化的。推断出进化的模式将使我们能够推断出一般的功能。Aim 2将使用基因组信息来研究P. carinii味精家族的表达，这一过程需要在一个独特的表达位点进行重组，从而导致表达基因序列的变化。大量证据表明，基因转换在表达的味精拷贝中产生了变异。目标2将探讨这一点和其他可能性。目的3将确定重组发生在鼠疟原虫DCS位点的频率。这些研究将建立小鼠作为研究肺囊虫抗原变异的模型，并为Aim 4中描述的研究奠定基础，该研究将验证适应性免疫反应可以影响位于表达位点的味精基因序列变异程度的观点。

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.