Regulation of Candida albicans gene expression in response to host environmental stresses

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PROJECT SUMMARY/ABSTRACT Candida albicans is a major human fungal pathogen responsible for a wide variety of systemic and mucosal infections. Immunocompromised individuals, including organ transplant recipients, AIDS patients and cancer patients on chemotherapy are highly susceptible to infection. In the host environment C. albicans encounters a wide variety of environmental stresses, including acidic pH, osmotic/cationic, thermal, oxidative, nitrosative, cell wall and cell membrane stresses. While transcriptional and post-translational mechanisms that mediate C. albicans stress responses have been well-characterized, considerably less is known about the role of translational mechanisms; given that many effective classes of antibiotics target bacterial translation mechanisms, this remains an unexplored and unexploited avenue for antifungal development. The eIF4F translation initiation complex is important for binding to the 5' CAP of mRNAs and contains helicase activity that unwinds complex secondary structures in 5' untranslated regions (UTRs) to promote translation and ribosome accessibility. We have recently demonstrated that fungal-specific C. albicans orthologs of the yeast eIF4E-binding proteins Eap1 and Caf20, which function as negative regulators of the eIF4F complex, play an important role in controlling oxidative and cell wall/cell membrane stress responses. In addition, we have shown that both C. albicans proteins are down-regulated in response to membrane stress and orf19.7034 (the Eap1 ortholog) functions as a key negative regulator of P-body formation under multiple stress conditions (P- bodies are translationally inactive cellular compartments). Using ribosome profiling, we have also recently demonstrated that the C. albicans morphological transition, and most likely additional virulence processes, is under widespread global translational control. Based on this evidence, and additional studies, our hypothesis is that elucidating translational regulatory mechanisms which control the ability of C. albicans to respond to host environmental stresses will provide a new strategy to identify and characterize potential antifungal targets. To address this hypothesis, we plan to: 1) determine the global translational profile of C. albicans in response to a variety of host environmental stress conditions; we will also identify and characterize selected translationally controlled target genes important for C. albicans stress responses, 2) determine how eIF4E-binding proteins and components of the eIF4F complex control the ability of C. albicans to respond to host environmental stresses, 3) determine how translational stress response mechanisms control C. albicans virulence and pathogenicity using both a mouse model of systemic candidiasis and macrophage/neutrophil killing and survival assays. These studies will provide a better understanding of global regulatory circuits and individual factors that control the translational response of C. albicans to host environmental stress conditions. Ultimately, common fungal-specific translation factors and/or target genes important for stress responses, virulence and pathogenesis could serve as important targets for the development of novel and more effective antifungals.