Fungal Virulence: Identifying the factors that control virulence and the growth in parasitic form of Coccidioides

真菌毒力：确定控制球孢子菌毒力和寄生形式生长的因素

• 批准号: 10356731
• 负责人: Sinem Beyhan
• 金额: $ 33.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-24 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356731
• 关键词: Adopted; Animal Model; Arizona; California; Candidate Disease Gene; Cell Culture Techniques; Central America; ChIP-seq; Coccidioides; Coccidioides immitis; Coccidioides posadasii; Coccidioidomycosis; Custom; Data; Engineering; Exhibits; Fibrinogen; Fungal Genes; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Goals; Growth; Immune Evasion; Immune response; Immune system; Immunocompromised Host; Immunogenetics; Infection; Knock-out; Light; Lung; Mexico; Molecular; Mouse Strains; Mus; Mycelium; Organism; Pathogenicity; Patients; Persons; Phenotype; Play; Pneumonia; Proteins; Proteome; Proteomics; Publishing; Reproduction spores; Resistance; Role; Rupture; Soil; South America; Southwestern United States; Structure; Surface; Testing; Transcript; Vertebrates; Virulence; Virulence Factors; base; cytokine; differential expression; exome; experimental study; functional genomics; fungus; genome-wide; infection rate; metabolome; mouse model; mutant; pathogen; response; transcription factor; transcriptome; transcriptome sequencing; transcriptomics

Abstract This Project will focus on the pathogen by undertaking transcriptomic, proteomic and genome-scale studies of Coccidioides species. Coccidioides species, C. immitis and C. posadasii, grow as a mycelium in the soil and differentiate into a unique round structure called a spherule in the mammalian host – a hallmark of their pathogenicity. Spherules enlarge and divide internally to form endospores which are released after about 4 days in the mammalian host. The mechanisms of differentiation into spherules and virulence factors of Coccidioides remain largely unknown. We are intrigued by the hypothesis that spherule-enriched genes and spherule surface- attached proteins are major players of the immune evasion strategies adopted by the pathogen. Therefore, in this Project, our overall goal is to identify genes/proteins that may play a role in (1) controlling transition from environmental-to-parasitic growth or (2) directly interacting with the host to subvert immune responses. We will take functional genomics and proteomic approaches to identify factors (i.e. transcriptional regulators) that are required for the expression of spherule-specific genes and endospore-specific genes and characterize them for their importance in spherule growth and spherule-specific gene expression profiles. In addition, we will identify fungal genes that are important for response to susceptible and resistant murine hosts, identify the secreted, surface-attached and/or GPI-anchored proteins from Coccidioides spherules, and generate knockout mutants of the candidate genes, which will be selected based on these transcriptomic and proteomics studies and our preliminary data. Mutants that show significant difference in eliciting cytokine response in cell culture will be prioritized to be tested for virulence phenotypes in mouse model of coccidioidomycosis under the activities planned in the Model Organism Core. Results of these experiments will reveal genes/proteins that are involved in regulating the parasitic growth of Coccidioides and shed light onto the molecular details of interactions between host and the pathogen.

抽象的 该项目将通过对病原体进行转录组学、蛋白质组学和基因组规模的研究来关注病原体。 球孢子菌属 (Coccidioides)、C. immitis 和 C. posadasii 在土壤中以菌丝体形式生长， 在哺乳动物宿主中分化成一种独特的圆形结构，称为小球——这是它们的标志 小球在内部扩大并分裂形成内生孢子，约4天后释放。 在哺乳动物宿主中分化成球孢子菌的小球和毒力因子的机制。 我们对小球富集基因和小球表面的假设很感兴趣。 附着蛋白是病原体采用的免疫逃避策略的主要参与者。 在这个项目中，我们的总体目标是识别可能在（1）控制从 环境到寄生虫的生长或（2）直接与宿主相互作用以破坏免疫反应。 采用功能基因组学和蛋白质组学方法来识别因子（即转录调节因子） 表达小球特异性基因和内生孢子特异性基因所需的基因，并对它们进行表征 它们在小球生长和小球特异性基因表达谱中的重要性此外，我们将确定。 真菌基因对于对易感和抗性小鼠宿主的反应很重要，可以识别分泌的、 来自球孢子菌小球的表面附着和/或 GPI 锚定蛋白，并产生以下基因的敲除突变体 候选基因，将根据这些转录组学和蛋白质组学研究以及我们的研究来选择 初步数据显示，在细胞培养物中引发细胞因子反应方面存在显着差异。 优先测试活动下球孢子菌病小鼠模型的毒力表型 这些实验的结果将揭示所涉及的基因/蛋白质。 调节球孢子菌的寄生生长，并揭示之间相互作用的分子细节 宿主和病原体。