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.

概括尽管目前可用有效的抗真菌毒剂，但仍然存在侵入性真菌感染疾病和死亡的高度普遍原因，尤其是在我们最脆弱的患者中免疫系统。艾滋病，器官移植和更具侵略性的癌症治疗都有助于持续扩展的患者群体，他们有这些严重感染的风险。未来的方向传染病的治疗将越来越多地涉及鉴定微生物特异性细胞过程可以针对干预。在此提案中，我们将研究人类真菌病原体中的中心信号通路在感染环境中诱导的隐孢子虫（CN）。我们开始研究 CN中的真菌特异性边缘信号通路作为表面胶囊表达和真菌的调节剂细胞健身。使用互补的转录组，蛋白质组学和微生物遗传技术，我们有在这种真菌病原体中，定义的RIM依赖性细胞事件允许快速微生物适应主机环境。这些适应中的许多是针对感染的pH的响应主持人。因此，我们的研究不仅针对微生物发病机理，而且还探索了中心真核细胞感知并响应这种重要的环境条件的方式。