Translational Control of Antifungal Resistance in Candida albicans

University Of Texas Hlth Science Center, San Antonio TX

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Abstract

PROJECT SUMMARY/ABSTRACT Candidiasis represents a leading cause of hospital?acquired bloodstream infections in the U.S. with an attributable mortality rate of 40-60%. Candida albicans, a major opportunistic human fungal pathogen responsible for the majority of candidiasis cases, can cause a wide variety of systemic and mucosal infections. Immunocompromised individuals, including organ transplant recipients, AIDS patients, and cancer patients on chemotherapy, are particularly susceptible. Currently, only three main classes of antifungals are available for the treatment of candidiasis, with azoles being the most widely used. As a result of repeated treatment of recurrent infections with current antifungals, as well as the use of long-term antibiotic prophylaxis, antifungal resistance, particularly to azoles, is on the rise and remains a clinically significant problem. While a number of transcriptional and post-translational mechanisms associated with C. albicans azole resistance have been well- characterized, considerably less is known about translational mechanisms. Importantly, studying translational control of C. albicans antifungal resistance is more likely to identify novel mechanisms, as well as translational regulatory events associated with currently known mechanisms, that have not been identified using previous approaches. Translational control is typically mediated by the 5' untranslated region of mRNAs. We have recently discovered that UME6, which encodes a key transcriptional regulator of C. albicans biofilm formation, morphology and virulence, possesses one of the longest 5' untranslated regions (UTRs) identified in fungi to date. The UME6 5' UTR inhibits C. albicans filamentation by specifically reducing translational efficiency. Interestingly, the level of translational inhibition appears to be modulated by host environmental signals. Importantly, a recent RNA sequencing analysis has also demonstrated that in addition to UME6, a significant number of C. albicans genes involved in other virulence-related processes, including antifungal drug resistance, possess long 5' UTR regions, suggesting that they are under translational control. 5' UTRs have also been shown to translationally regulate a wide variety of additional biological processes in higher eukaryotes. Based on this evidence, our hypothesis is that translational efficiency mechanisms play an important role in controlling C. albicans antifungal resistance. In order to test this hypothesis we plan to perform experiments designed to address the following specific aims: 1) determine the global translational profile of C. albicans in response to fluconazole treatment, 2) identify and characterize translational mechanisms specifically associated with C. albicans azole resistance. Ultimately, the proposed studies will provide a better understanding of global regulatory circuits and pathways that control C. albicans azole resistance at the translational level. These studies will also identify several key translationally regulated proteins important for azole resistance that could potentially serve as targets for novel therapies and/or drug treatment regimens.