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.

霉菌病原体烟曲霉感染仍然是有效治疗的主要障碍。免疫功能低下患者的管理，特别是患有血液系统恶性肿瘤、器官疾病的患者移植、慢性肉芽肿性疾病或囊性纤维化。尽管我们的理解取得了一些进步对于这种感染，目前尚不清楚这种真菌如何如此容易地适应宿主环境并逃脱清除在长期殖民的情况下。未折叠蛋白反应 (UPR) 是一种信号通路，可感知内质网 (ER) 上的压力负荷并将该信息传递给细胞核。当前的有证据表明，AF 和其他病原真菌严重依赖 UPR 来支持毒力和抗真菌药物耐药性。然而，实现这一目标的机制并不完整明白了。本次资助的初步数据为 UPR 功能的新机制提供了证据涉及细胞质 Ca2+ 水平的调节，以响应 AF 必须适应的两种应激条件宿主：（1）由于分泌途径需求增加而导致内质网稳态丧失，以及（2）直接受到先天免疫系统细胞的攻击。由于 Ca2+ 是一种有效的第二信使，这些发现表明 UPR 与信号通路整合，将细胞质 Ca2+ 信号解码为宿主适应性回应。我们提出了三个目标来确定 AF 适应这些压力源的机制；目的 1 将确定 ER 应激期间 UPR 如何与 Ca2+ 信号传导相关以及它与钙调神经磷酸酶的关系激活和毒力，目标 2 将确定先天免疫系统细胞触发的机制 Ca2+ 流入真菌并阐明这些事件对真菌存活的影响。最后，Aim 3 将使用描述对中性粒细胞的全基因组转录和翻译反应的公正方法攻击，以及它们对 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对宿主的适应，这将为未来增强宿主的治疗策略铺平道路清理机制。

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.