ER stress and virulence of Aspergillus fumigatus

描述（由申请方提供）：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性霉菌。尽管在治疗方面取得了一些进展，但侵袭性曲霉病的预后仍然很差，这强调了需要更多关于真菌途径的信息，这些途径对生物体在体内的生长至关重要。A.烟曲霉分泌大量细胞外蛋白作为其正常腐生生活方式的一部分，这使其面临蛋白质解折叠和内质网（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、分泌和降解的基因的表达来对抗这种压力。在本研究中，我们提供了A.烟曲霉在很大程度上依赖于UPR来支持其在内质网应激下生存并从宿主组织获取营养所需的分泌活性。其次，我们证明了UPR功能的丧失与现有的抗真菌药物对A。烟熏。使用UPR和相关ER相关降解途径（ERAD）的突变体，我们建议验证ER应激反应作为曲霉病的治疗靶点，并深入了解反应的关键组成部分。本文提出了以下具体目的：目的一是检验普遍定期审议对A.在ER应激的条件下，它可以抑制烟曲霉，并且它有助于生物体在体内引起疾病的能力。目的II将测试ERAD也需要在ER应激条件下维持生长的假设，并且它与UPR协同工作以支持生物体在体内的毒力。Aim III将使用全基因组方法来鉴定A.烟曲霉内质网应激反应的研究。烟曲霉对内质网应激的反应涉及一组mRNA转录和翻译的特异性变化。这些研究有可能确定治疗曲霉病的新靶点，并对增加对现有抗真菌药物具有内在耐药性的真菌物种的抗真菌药敏谱具有更广泛的意义。

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.