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

• 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
• 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

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

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

P5型ATPase SPFA对应力反应网络的多效性作用有助于致病性霉菌曲霉的毒力。

• 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.

• DOI: 10.1128/msphere.00879-20
• 发表时间: 2020-10-21
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Guirao-Abad JP;Weichert M;Albee A;Deck K;Askew DS
• 通讯作者: Askew DS