TRANSLATIONAL CONTROL OF BIOFILM DEVELOPMENT AND MAINTENANCE IN ORAL CANDIDIASIS

Candidiasis has remained the most common opportunistic oral infection in HIV positive individuals and AIDSpatients. Even following the introduction of highly active antiretroviral therapy (HAART) approximately 30% ofAIDS patients acquire oropharyngeal candidiasis (OPC). Candida albicans, the main causative agent of OPC,forms complex aggregated microbial communities, known as biofilms, on host oral mucosal surfaces whichplay an important role in establishing infections called ?oral thrush?. C. albicans biofilms are highly resistant toantifungals, serve as important reservoirs for infection and, if not treated effectively, can result in more serioussystemic infections. In order to develop more effective anti-biofilm therapies to treat HIV/AIDS patients withOPC, it is important to first gain a comprehensive understanding of regulators and target genes that control C.albicans biofilm development and maintenance. While a significant amount of research has focused ontranscriptional and post-translational mechanisms that regulate C. albicans biofilm development, considerablylittle is known about post-transcriptional, and particularly translational, mechanisms. Importantly, studyingtranslational control of C. albicans biofilm development and maintenance is also more likely to identify novelpotential anti-biofilm targets that have not been discovered using previous approaches. We have recentlydiscovered 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, which is important for biofilm development, byspecifically reducing translational efficiency. Interestingly, the level of translational inhibition appears to bemodulated by host environmental signals. A recent RNA sequencing analysis has also demonstrated that inaddition to UME6, a significant number of C. albicans genes involved in biofilm development and othervirulence-related processes also possess long 5' UTRs. Based on this evidence, our hypothesis is thattranslational efficiency mechanisms play an important role in controlling C. albicans biofilm development,maintenance and pathogenicity. To address this hypothesis we plan to: 1) use a powerful new globalapproach, ribosome profiling, to identify the complete set of C. albicans genes showing changes intranslational efficiency that are specifically associated with biofilm development and/or maintenance, 2)characterize selected translationally regulated C. albicans genes that play novel roles in biofilm developmentand/or maintenance both in vitro and in a mouse model of oral candidiasis. Ultimately, the proposed studieswill provide a better understanding of global regulatory circuits and pathways that control C. albicans biofilmdevelopment and maintenance at the translational level and identify several key proteins that could potentiallyserve as targets for the development of new and more effective therapies to treat immunocompromisedHIV/AIDS patients with oral candidiasis.