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Coordinated responses to host-derived stresses in C. neoformans

新型隐球菌对宿主应激的协调反应

基本信息

批准号：
10637411
负责人：
ANDREW ALSPAUGH
金额：
$ 36.02万
依托单位：
DUKE UNIVERSITY
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：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10637411
关键词：
Acquired Immunodeficiency Syndrome Address Antifungal Agents Applications Grants Arrestins Basidiomycota Biochemical Cell Wall Cell membrane Cell physiology Cell surface Cells Cellular Stress Cessation of life Collection Complex Cryptococcus neoformans Data Disease Drug Tolerance Environment Eukaryotic Cell Event Future Genetic Genetic Screening Genetic Techniques Goals Human Immune Immune response Immune system Impairment In Vitro Infection Intervention Mediating Microbe Microbial Genetics Modeling Molecular Mycoses Nutrient availability Organ Transplantation Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Phosphorylation Plasma Cells Post-Translational Protein Processing Prevention Process Proteins Proteomics Regulation Research Personnel Risk Signal Pathway Signal Transduction Stress Surface System Testing Ubiquitin Ubiquitination Variant Virulence antimicrobial cancer therapy capsule comparative experimental study extracellular fitness fungus genetic manipulation in vivo in vivo Model infectious disease treatment microbial microbial host microorganism mutant novel opportunistic pathogen optimal treatments pathogenic fungus pathogenic microbe pharmacologic response scaffold screening sensor trafficking transcriptomics ubiquitin ligase ubiquitin-protein ligase

项目摘要

SUMMARY Although potent antifungal agents are currently available, invasive fungal infections remain highly prevalent causes of disease and death, especially in our most vulnerable patients with defective immune systems. AIDS, organ transplantation, and more aggressive cancer treatments all contribute to ever-expanding patient groups who are at risk for these serious infections. Future directions in the treatment of infectious diseases will increasingly involve identifying microbe-specific cellular processes that can be targeted for intervention. In this proposal, we will study central signaling pathways in the human fungal pathogen Cryptococcus neoformans (Cn) that are induced in the setting of infection. We began studying the fungal-specific Rim signaling pathway in Cn as a regulator of surface capsule expression and fungal cell fitness. Using complementary transcriptomic, proteomic, and microbial genetic techniques, we have defined Rim-dependent cellular events in this fungal pathogen that allow rapid microbial adaptation to the host environment. Many of these adaptations occur specifically in response to the pH of the infected host. Therefore, our studies not only address microbial pathogenesis, but they also explore central ways in which eukaryotic cells sense and respond to this important environmental condition.

摘要尽管目前已有有效的抗真菌药物，但侵袭性真菌感染仍然存在。疾病和死亡的高流行原因，特别是在我们最脆弱的缺陷患者中免疫系统。艾滋病、器官移植和更激进的癌症治疗都有助于不断扩大的患者群体，他们面临这些严重感染的风险。未来的发展方向传染病的治疗将越来越多地涉及识别特定于微生物的细胞过程。这可以成为干预的目标。在这项计划中，我们将研究人类真菌病原体的中心信号通路。在感染环境中诱导的新生隐球菌(CN)。我们开始研究 CN中真菌特异的Rim信号通路作为表面被膜表达和真菌的调节细胞健康。利用互补的转录、蛋白质组和微生物遗传技术，我们已经这种真菌病原体中明确的环状依赖细胞事件，使微生物能够快速适应主机环境。这些适应中的许多都是专门针对感染者的PH值而发生的主持人。因此，我们的研究不仅涉及微生物的发病机制，而且还探索了真核细胞感知和响应这一重要环境条件的方式。