Role of the OPI1 gene in controlling viability of Candida glabrata

描述（由申请人提供）：念珠菌是50-90%获得性免疫缺陷综合征（AIDS）患者口腔真菌感染的原因。由于采用了高效抗逆转录病毒疗法（HAART），艾滋病更易于控制。然而，随着HAART治疗人群的老龄化，老年人类免疫缺陷病毒（HIV）阳性患者的需求将成为一个非常重要的问题，因为免疫功能将下降。这些患者可能会出现口腔念珠菌感染的增加，这是痛苦的，有时使人虚弱。这种念珠菌感染最常见的原因是白色念珠菌，然而，非白色念珠菌物种已经成为一个日益严重的问题，在某些类型的感染中几乎经常发生。例如，从HIV阳性的假牙口炎患者中分离出的光念珠菌几乎与白色念珠菌一样多（分别为41.3%和48.8%）。口干舌燥是一种与药物或老年人常见病相关的副作用，故适用于口干舌燥患者。假牙、免疫抑制和与HIV阳性人口老龄化相关的口干的结合将越来越有利于已经上升的光齿锥体感染频率。常用的抗真菌药物有三种：唑类、多烯类和棘白菌素类。C. glabrata是不寻常的，因为它天生对唑类抗真菌药更有抵抗力。此外，也发现了对其他种类的药物也有抗药性。这些事实突出了发现新的抗真菌药物的必要性。一种新的抗真菌药物的理想候选物将抑制光棘球霉中一种对生存至关重要的蛋白质，而这种蛋白质在人类宿主中没有密切的同源物。我们已经鉴定出一种叫做CgOpi1p的蛋白质，它是C. glabrata生存所必需的。重要的是，它没有人类同源物，因此它可能是一个有用的药物靶点。我们打算更好地理解CgOpi1p是可行性所必需的机制。CgOpi1p与面包酵母中的Opi1p蛋白相似。酿酒葡萄球菌Opi1p抑制一些在磷脂生物合成中重要的基因的表达。磷脂是构建细胞膜所必需的，是生命所必需的。在葡萄球菌中，生存能力不需要Opi1p。我们的假设是CgOpi1p，像酿酒酵母一样，抑制磷脂生物合成基因，但在C. glabrata中，由于一些脂质生物合成基因的产生增加，缺乏抑制是致命的。我们将通过两个具体目标来解决这个假设：1。我们将确定CgOpi1p是否控制磷脂生物合成基因的表达。2. 我们将确定由CgOpi1p调控的基因突变是否会抑制细胞的生存缺陷。初步结果表明情况确实如此。念珠菌在50-90%的获得性免疫缺陷综合征（AIDS）患者中引起口腔感染。光齿c是老年人和假牙患者的常见感染源。它对被称为唑类的三种主要抗真菌药物中的一种具有特别的耐药性，并且已经发现的分离物也对其他主要类别具有耐药性，这突出了寻找新型抗真菌药物的重要性。

DESCRIPTION (provided by applicant): Candida species are the cause oral fungal infections in 50-90% of patients that have Acquired Immune Deficiency Syndrome (AIDS). AIDS is more manageable due to the introduction of Highly Active Antiretroviral Therapy (HAART). However, as the population of patients treated by HAART ages, the needs of elderly Human Immunodeficiency Virus (HIV) positive patients will become a very important concern because immune function will decline. These patients may see an increase in oral Candida infections, which are painful and sometimes debilitating. The most common cause of such Candida infections is Candida albicans, however non-albicans species have been a growing problem, and in some types of infections occur nearly as often. For example, Candida glabrata was isolated from HIV positive patients with denture stomatitis nearly as often as C. albicans (41.3% and 48.8%, respectively). C. glabrata is favored in patients with dryness of mouth, which is a side effect associated with medications or conditions frequently found in the elderly. The combination of dentures, immunosuppression, and dryness of mouth associated with an aging HIV positive population will increasingly favor the already rising frequency of C. glabrata infections. There are three classes of antifungals in common use against Candida infections, the azoles, the polyenes, and the echinocandins. C. glabrata is unusual in that it is innately more resistant to the azole class of antifungals. In addition, C. glabrata isolates have been found that are resistant to the other classes of drugs as well. These facts highlight the need to identify new antifungal agents. The ideal candidate for a new antifungal drug will inhibit a protein in C. glabrata that is essential for viability that does not have a close homolog in the human host. We have identified a protein called CgOpi1p that is required for viability in C. glabrata. Importantly, it has no human homologs, thus it could be a useful drug target. We intend to better understand the mechanism(s) by which CgOpi1p is required for viability. CgOpi1p is similar to the Opi1p protein in the bakers' yeast Saccharomyces cerevisiae. S. cerevisiae Opi1p represses the expression of a number of genes that are important in phospholipid biosynthesis. Phospholipids are required for construction of the cell's membrane, and are essential for life. In S. cerevisiae Opi1p is not required for viability. Our hypothesis is that CgOpi1p, like S. cerevisiae Opi1p, represses phospholipid biosynthetic genes, but in C. glabrata, a lack of repression is lethal due to increased production of some lipid biosynthetic gene. We will address this hypothesis by two specific aims: 1. We will determine if CgOpi1p controls expression of phospholipid biosynthetic genes. 2. We will determine if mutations in genes regulated by CgOpi1p will suppress the cell's viability defect. Preliminary results suggest that this is the case. Candida species cause oral infections in 50-90% of Acquired Immunodeficiency Syndrome (AIDS) patients. The species C. glabrata is a common source of infection in the elderly and patients with dentures. It is particularly resistant to one of the three major classes of antifungal agents called the azoles, and isolates have been discovered that are resistant to the other main classes as well, which highlights the importance of finding new classes of antifungal agents.