Translational repression & Aspergillus fumigatus virulence

转化抑制

• 批准号: 8681609
• 负责人: DAVID S ASKEW
• 金额: $ 22.31万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681609
• 关键词: Antifungal Agents; Antifungal Therapy; Aspergillus fumigatus; Characteristics; Data; Development; Disease; Endoplasmic Reticulum; Environment; Eukaryotic Initiation Factors; Fractionation; Future; Generations; Genes; Genome; Hematologic Neoplasms; Homeostasis; Homologous Gene; In Vitro; Infection; Lead; Life; Lung; Mammals; Mediating; Messenger RNA; Molds; Mutation; Nature; Organ Transplantation; Organelles; Organism; Outcome; Outcome Study; Pathogenicity; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Physiology; Polyribosomes; Predisposition; Prokaryotic Initiation Factor-2; Protein Biosynthesis; Proteins; Reliance; Repression; Resistance; Serine; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Translational Repression; Translations; Virulence; Work; Workload; biological adaptation to stress; cell type; combat; endoplasmic reticulum stress; fungus; insight; mortality; mutant; novel; novel strategies; outcome forecast; pathogen; prevent; protein folding; public health relevance; response; restoration; sensor; trait; transcription factor; transcriptome sequencing

DESCRIPTION (provided by applicant): Infections with the opportunistic mold Aspergillus fumigatus continue to be a major threat to the management of patients with hematologic malignancies and organ transplants. Since current antifungal therapies are unable to prevent a high rate of mortality for this disease, there is a need for more information on fungal pathways that allow this organism to thrive in the host environment. Recent studies have shown that A. fumigatus, and other pathogenic fungi, rely heavily on the unfolded protein response (UPR) for infection. The UPR is an adaptive response to endoplasmic reticulum (ER) stress, responsible for adjusting the protein folding capacity of the ER in proportion to the demand placed on the secretory pathway. In mammals, an important branch of the UPR is translational repression mediated by eIF2¿ phosphorylation, a pathway that lowers the influx of nascent proteins into the ER when the organelle is overloaded. Our preliminary data demonstrate that an analogous pathway is present in A. fumigatus, which challenges the existing paradigm of fungal UPR signaling. The overarching hypothesis to be tested in this proposal is that translational repression is a vital stress response of A. fumigatus that contributes to the virulence and antifungal drug susceptibility of this organism. The first aim will use mutants of the pathway to determine the impact of eIF2¿ phosphorylation and translational repression on the ability of the fungus to cause infection and to withstand antifungal drugs and other types of stress. Secondly, an important characteristic of the mammalian pathway is that a limited subset of mRNAs with key functions in ER homeostasis can escape translational repression. Thus, a second aim will use RNA-seq and polysome fractionation to identify mRNAs that show increased translation during ER stress. The outcome of this study is expected to uncover a new paradigm for the fungal ER stress response, which could lead to the development of novel strategies to combat infections with A. fumigatus, and potentially other eukaryotic pathogens that exploit the UPR for virulence.

描述（由适用提供）：机会性霉菌曲霉的感染仍然是对血液学恶性肿瘤和器官移植患者管理的主要威胁。由于目前的抗真菌疗法无法预防这种疾病的高死亡率，因此需要更多有关真菌途径的信息，以使该生物可以在宿主环境中蓬勃发展。最近的研究表明，Fumigatus和其他致病真菌在很大程度上依赖于展开的蛋白质反应（UPR）进行感染。 UPR是对内质网（ER）应力的自适应反应，负责调整ER的蛋白质折叠能力，这与秘密途径上的需求成比例。在哺乳动物中，将UPR的重要分支翻译为EIF2¿磷酸化介导的表示，这是一种途径，该途径降低了当细胞器过载时，降低了新生蛋白到ER的影响。我们的初步数据表明，烟曲霉中存在类似的途径，这挑战了真菌UPR信号的现有范式。在该提案中要检验的总体假设是，翻译表达是烟曲霉的重要应激反应，有助于该生物的病毒和抗真菌药物的敏感性。第一个目的将使用途径的突变体来确定EIF2磷酸化和翻译表达对真菌引起感染和承受抗真菌药物和其他类型压力的能力的影响。其次，哺乳动物途径的一个重要特征是，在ER稳态中具有关键功能的mRNA子集有限的子集可以逃避翻译表达。这是第二个目标将使用RNA-seq和多质体分馏来识别在ER应力期间的翻译增加的mRNA。这项研究的结果有望发现真菌ER应激反应的新范式，这可能导致开发新的策略，以用烟曲霉对抗感染，以及可能将UPR剥削为病毒的其他真核生物病原体。