ER stress and calcium in host adaptation of A. fumigatus

烟曲霉宿主适应中的内质网应激和钙

基本信息

批准号：
9979741
负责人：
DAVID S ASKEW
金额：
$ 41.53万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-27 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979741
关键词：
ATP phosphohydrolase Acute Affect Affinity Chromatography Antifungal Agents Aspergillosis Aspergillus fumigatus Asthma Atmosphere Azoles Calcineurin Calcineurin Pathway Calcium Cell Communication Cell Nucleus Cells Chronic Chronic Granulomatous Disease Cystic Fibrosis Data Dependence Disease Drug Exposure Endoplasmic Reticulum Environment Event Foundations Fungal Drug Resistance Future Genetic Transcription Goals Grant Hematologic Neoplasms Homeostasis Host Defense Human Immune Evasion Immune system Immunocompromised Host Impairment Infection Inflammation Inhalation Innate Immune System Intervention Laboratories Lead Life Link Lung infections Membrane Molds Morbidity - disease rate Mucous body substance Nucleotides Organ Transplantation Outcome Outcome Study Output Pathogenesis Pathway interactions Protein Isoforms Proteins Pump Regulation Reproduction spores Role Second Messenger Systems Signal Pathway Signal Transduction Solid Specificity Stress Testing Therapeutic Transcript Virulence biological adaptation to stress cell type cystic fibrosis patients design endoplasmic reticulum stress fungus genome-wide insight live cell imaging mortality mouse model mutant neutrophil novel pathogen pathogenic fungus protein protein interaction pulmonary function respiratory colonization response stressor transcriptome sequencing

项目摘要

Infections with the mold pathogen Aspergillus fumigatus continue to be a major obstacle to the effective management of immunocompromised patients, particularly those with hematologic malignancies, organ transplants, chronic granulomatous disease, or cystic fibrosis. Despite several advances in our understanding of this infection, it is unclear how this fungus adapts so readily to the host environment, and escapes clearance in situations of chronic colonization. The unfolded protein response (UPR) is a signaling pathway that senses the stress load on the endoplasmic reticulum (ER) and communicates that information to the nucleus. Current evidence indicates that AF, and other pathogenic fungi, rely heavily on the UPR to support virulence and antifungal drug resistance. However, the mechanisms by which this is accomplished are incompletely understood. The preliminary data in this grant provide evidence for a new mechanism of UPR function that involves the regulation of cytoplasmic Ca2+ levels in response to two stress conditions that AF must adapt to in the host: (1) loss of ER homeostasis caused by increased demand on the secretory pathway, and (2) direct attack by cells of the innate immune system. Since Ca2+ is a potent second messenger, these findings suggest that the UPR integrates with signaling pathways that decode cytoplasmic Ca2+ signatures into host adaptive responses. We propose three aims to determine the mechanisms by which AF adapts to these stressors; Aim 1 will establish how the UPR links to Ca2+ signaling during ER stress and the relationship it has to calcineurin activation and virulence, Aim 2 will identify the mechanism by which cells of the innate immune system trigger Ca2+ influx into the fungus and elucidate the impact of these events on fungal survival. Lastly, Aim 3 will use an unbiased approach to delineate the genome-wide transcriptional and translational responses to neutrophil attack, and their dependency upon Ca2+ signaling. The outcome of this study will reveal new mechanisms of host adaptation by this fungus, which will pave the way for future therapeutic strategies to augment host clearance mechanisms.

霉菌病原体曲霉的感染仍然是有效的主要障碍管理免疫功能低下的患者，特别是患有血液学恶性肿瘤的患者移植，慢性肉芽肿或囊性纤维化。尽管我们的理解取得了一些进步在这种感染中，目前尚不清楚这种真菌如何如此轻松地适应主机环境，并逃脱了清除在慢性定植的情况下。展开的蛋白质反应（UPR）是一种感应的信号通路内质网（ER）上的应力载荷，并将这些信息传达给细胞核。当前的证据表明，AF和其他致病真菌在很大程度上依赖UPR来支持毒力和抗真菌耐药性。但是，实现这一目标的机制是不完整的理解。该赠款中的初步数据为UPR功能的新机制提供了证据涉及对AF必须适应的两个应力条件的细胞质Ca2+水平的调节主机：（1）因分泌途径的需求增加而导致ER稳态的丧失，以及（2）直接先天免疫系统的细胞攻击。由于CA2+是有效的第二使者，因此这些发现表明 UPR与将细胞质Ca2+签名解码为宿主自适应的信号通路集成回答。我们提出了三个目的，以确定AF适应这些压力源的机制。目的 1将确定UPR在ER应力期间如何链接到Ca2+信号传导及其与钙调神经酶的关系激活和毒力，AIM 2将确定先天免疫系统触发细胞的机制 Ca2+涌入真菌，并阐明这些事件对真菌存活的影响。最后，AIM 3将使用一种无偏见的方法来描述全基因组的转录和对中性粒细胞的翻译反应攻击及其对CA2+信号传导的依赖。这项研究的结果将揭示新的机制这种真菌的宿主改编将为未来的治疗策略铺平道路增强宿主清除机制。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pleiotropic Effects of the P5-Type ATPase SpfA on Stress Response Networks Contribute to Virulence in the Pathogenic Mold Aspergillus fumigatus.

DOI：
10.1128/mbio.02735-21
发表时间：
2021-10-26
期刊：
mBio
影响因子：
6.4
作者：
Guirao-Abad JP;Weichert M;Luengo-Gil G;Sze Wah Wong S;Aimanianda V;Grisham C;Malev N;Reddy S;Woollett L;Askew DS
通讯作者：
Askew DS

A Human IRE1 Inhibitor Blocks the Unfolded Protein Response in the Pathogenic Fungus Aspergillus fumigatus and Suggests Noncanonical Functions within the Pathway.