Role of the OPI1 gene in controlling viability of Candida glabrata

University Of Tennessee Knoxville, Knoxville TN

Investigators

Linked publications & trials

Abstract

[unreadable] 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. [unreadable] [unreadable] [unreadable]