TRANSLATIONAL CONTROL OF ANTIFUNGAL RESISTANCE IN CANDIDA ALBICANS

Candidiasis represents a leading cause of hospital?acquired bloodstream infections in the U.S. with anattributable mortality rate of 40-60%. Candida albicans, a major opportunistic human fungal pathogenresponsible 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 onchemotherapy, are particularly susceptible. Currently, only three main classes of antifungals are available forthe treatment of candidiasis, with azoles being the most widely used. As a result of repeated treatment ofrecurrent infections with current antifungals, as well as the use of long-term antibiotic prophylaxis, antifungalresistance, particularly to azoles, is on the rise and remains a clinically significant problem. While a number oftranscriptional and post-translational mechanisms associated with C. albicans azole resistance have been well-characterized, considerably less is known about translational mechanisms. Importantly, studying translationalcontrol of C. albicans antifungal resistance is more likely to identify novel mechanisms, as well as translationalregulatory events associated with currently known mechanisms, that have not been identified using previousapproaches. Translational control is typically mediated by the 5' untranslated region of mRNAs. We haverecently 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 todate. 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 significantnumber of C. albicans genes involved in other virulence-related processes, including antifungal drugresistance, possess long 5' UTR regions, suggesting that they are under translational control. 5' UTRs havealso been shown to translationally regulate a wide variety of additional biological processes in highereukaryotes. Based on this evidence, our hypothesis is that translational efficiency mechanisms play animportant role in controlling C. albicans antifungal resistance. In order to test this hypothesis we plan toperform experiments designed to address the following specific aims: 1) determine the global translationalprofile of C. albicans in response to fluconazole treatment, 2) identify and characterize translationalmechanisms specifically associated with C. albicans azole resistance. Ultimately, the proposed studies willprovide a better understanding of global regulatory circuits and pathways that control C. albicans azoleresistance at the translational level. These studies will also identify several key translationally regulatedproteins important for azole resistance that could potentially serve as targets for novel therapies and/or drugtreatment regimens.