Candidiasis has remained the most common opportunistic oral infection in HIV positive individuals and AIDS patients. Even following the introduction of highly active antiretroviral therapy (HAART) approximately 30% of AIDS 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 which play an important role in establishing infections called ?oral thrush?. C. albicans biofilms are highly resistant to antifungals, serve as important reservoirs for infection and, if not treated effectively, can result in more serious systemic infections. In order to develop more effective anti-biofilm therapies to treat HIV/AIDS patients with OPC, 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 on transcriptional and post-translational mechanisms that regulate C. albicans biofilm development, considerably little is known about post-transcriptional, and particularly translational, mechanisms. Importantly, studying translational control of C. albicans biofilm development and maintenance is also more likely to identify novel potential anti-biofilm targets that have not been discovered using previous approaches. 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, which is important for biofilm development, by specifically reducing translational efficiency. Interestingly, the level of translational inhibition appears to be modulated by host environmental signals. A recent RNA sequencing analysis has also demonstrated that in addition to UME6, a significant number of C. albicans genes involved in biofilm development and other virulence-related processes also possess long 5' UTRs. Based on this evidence, our hypothesis is that translational 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 global approach, ribosome profiling, to identify the complete set of C. albicans genes showing changes in translational 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 development and/or maintenance both in vitro and in a mouse model of oral candidiasis. Ultimately, the proposed studies will provide a better understanding of global regulatory circuits and pathways that control C. albicans biofilm development and maintenance at the translational level and identify several key proteins that could potentially serve as targets for the development of new and more effective therapies to treat immunocompromised HIV/AIDS patients with oral candidiasis.
Relevance to public health: Candidiasis, the most common opportunistic oral infection in immunocompromised HIV/AIDS patients, is closely associated with the ability of the major human fungal pathogen Candida albicans to develop and maintain complex surface-attached aggregated microbial communities known as biofilms. This proposal will determine the role that translational efficiency mechanisms play in promoting C. albicans biofilm development, maintenance and pathogenicity. Ultimately, this study will identify new potential targets for the development of novel and more effective therapies to treat HIV/AIDS patients with oral candidiasis.