ER stress and virulence of Aspergillus fumigatus

烟曲霉的内质网应激和毒力

• 批准号: 7739483
• 负责人: DAVID S ASKEW
• 金额: $ 34.75万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739483
• 关键词: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Data; Degradation Pathway; Disease; Endoplasmic Reticulum; Endoplasmic Reticulum Degradation Pathway; Exhibits; Extracellular Protein; Gene Expression; Genetic Transcription; Grant; Growth; Immunocompromised Host; Life Style; Molds; Nutrient; Organism; Outcome; Pathway interactions; Predisposition; Proteins; Research Personnel; Resistance; Stress; Testing; Tissues; Translations; Virulence; Work; biological adaptation to stress; endoplasmic reticulum stress; genome-wide; high risk; in vivo; insight; mutant; novel; pathogen; protein folding; response; synergism; therapeutic target

DESCRIPTION (provided by applicant): Aspergillus fumigatus is an important opportunistic fungal pathogen that has become the leading infectious mould of immunocompromised patients. Despite some advances in therapy, invasive aspergillosis continues to have a poor outcome, emphasizing the need for more information on fungal pathways that are essential to the growth of the organism in vivo. A. fumigatus secretes tremendous quantities of extracellular proteins as part of its normal saprophytic lifestyle, which places it at high risk for protein unfolding and endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) counters this stress by upregulating the expression of genes involved in protein folding, secretion and degradation. In this grant, we provide preliminary data that A. fumigatus relies heavily upon the UPR to support the secretory activity that it needs to survive ER stress and acquire nutrients from host tissue. Secondly, we demonstrate that loss of UPR function exhibits potent synergism with existing antifungal drugs against A. fumigatus. Using mutants of the UPR and the related ER- associated degradation pathway (ERAD), we propose to validate ER stress responses as a therapeutic target for aspergillosis, and to gain insight into the key components of the response. The following specific Aims are proposed: Aim I will test the hypothesis that the UPR is essential for the growth of A. fumigatus under conditions of ER stress, and that it contributes to the ability of the organism to cause disease in vivo. Aim II will test the hypothesis that ERAD is also required to sustain growth under conditions of ER stress, and that it works in concert with the UPR to support the virulence of the organism in vivo. Aim III will use a genome-wide approach to identify novel components of the A. fumigatus ER stress response by testing the hypothesis that the response of A. fumigatus to ER stress involves specific changes in the transcription and translation of a subset of mRNAs. These studies have the potential to identify novel targets for the treatment of aspergillosis, and have broader implications for increasing the antifungal susceptibility profile of fungal species that are intrinsically resistant to existing antifungals.

描述（由申请人提供）：烟曲霉是一种重要的机会性真菌病原体，已成为免疫功能低下患者的主要感染霉菌。尽管治疗取得了一些进展，但侵袭性曲霉病的治疗效果仍然不佳，这强调需要更多关于真菌途径的信息，这些途径对于有机体在体内的生长至关重要。作为其正常腐生生活方式的一部分，烟曲霉会分泌大量的细胞外蛋白质，这使其面临蛋白质展开和内质网 (ER) 应激的高风险。未折叠蛋白反应（UPR）通过上调参与蛋白质折叠、分泌和降解的基因表达来对抗这种应激。在这笔资助中，我们提供了初步数据，表明烟曲霉严重依赖 UPR 来支持其生存 ER 应激和从宿主组织获取营养所需的分泌活动。其次，我们证明UPR功能的丧失与现有的针对烟曲霉的抗真菌药物表现出有效的协同作用。利用 UPR 和相关 ER 相关降解途径 (ERAD) 的突变体，我们建议验证 ER 应激反应作为曲霉菌病的治疗靶点，并深入了解该反应的关键组成部分。提出以下具体目标： 目标 I 将检验以下假设：UPR 对于 ER 应激条件下烟曲霉的生长至关重要，并且它有助于生物体在体内引起疾病的能力。目标 II 将检验以下假设：ERAD 也需要在内质网应激条件下维持生长，并且它与 UPR 协同作用以支持生物体体内的毒力。 Aim III 将使用全基因组方法，通过测试烟曲霉对 ER 应激反应涉及 mRNA 子集的转录和翻译的特定变化这一假设，来鉴定烟曲霉 ER 应激反应的新成分。这些研究有可能确定治疗曲霉病的新靶标，并对提高对现有抗真菌药物具有内在耐药性的真菌物种的抗真菌敏感性具有更广泛的影响。