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

白色念珠菌基因表达响应宿主环境胁迫的调节

基本信息

批准号：
10867738
负责人：
DAVID KADOSH
金额：
$ 58.2万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10867738
关键词：
5&apos Untranslated Regions Acquired Immunodeficiency Syndrome Address Affect Antibiotics Antifungal Agents Binding Binding Proteins Bioinformatics Biological Assay Cancer Patient Candida albicans Candidiasis Cell Wall Cell membrane Complex Cryptococcus neoformans Defect Development Disseminated candidiasis EIF-2alpha Environment Epitopes Eukaryotic Initiation Factor-4F Fungal Drug Resistance Gene Expression Genes Genetic Transcription Goals Growth HIV/AIDS Hospitals Human Immune Immunocompromised Host Individual Infection Link Macrophage Mediating Membrane Messenger RNA Morphology Mucous Membrane Mutation Orthologous Gene Osmosis Oxidative Stress Pathogenesis Pathogenicity Patients Phagocytes Phosphorylation Phosphotransferases Play Predisposition Process Proteins Public Health Regulation Ribosomes Role Saccharomyces cerevisiae Sepsis Signal Pathway Stress Structure Systemic infection Testing Transcript Translational Regulation Translations Virulence Yeasts biological adaptation to stress chemotherapy combat environmental stressor experimental study genome-wide helicase mRNA capping mouse model mutant neutrophil new therapeutic target novel novel therapeutic intervention organ transplant recipient pathogenic fungus prevent protein function response ribosome profiling translation factor treatment strategy

项目摘要

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.

项目总结/文摘