ER stress and calcium in host adaptation of A. fumigatus

霉菌病原体烟曲霉的感染仍然是有效治疗的主要障碍。 管理免疫功能低下的患者，特别是那些患有血液恶性肿瘤，器官 移植、慢性肉芽肿性疾病或囊性纤维化。尽管我们在理解上有了一些进步 目前还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， 应激负荷在内质网（ER）上并将该信息传递到细胞核。电流 有证据表明，AF和其他病原真菌严重依赖UPR来支持毒力， 抗真菌药物耐药性。然而，实现这一点的机制是不完全的。 明白该赠款中的初步数据为普遍定期审议的新机制提供了证据， 涉及调节细胞质Ca 2+水平，以响应AF必须适应的两种胁迫条件， 宿主：（1）对分泌途径的需求增加导致ER稳态丧失，和（2）直接 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，该信号通路将细胞质Ca 2+信号解码为宿主适应性信号。 应答我们提出了三个目标来确定AF适应这些压力的机制： 1将建立在ER应激过程中UPR如何与Ca2+信号转导联系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+流入真菌和阐明这些事件对真菌生存的影响。最后，Aim 3将使用 一种描述对中性粒细胞的全基因组转录和翻译反应的无偏方法 攻击，以及它们对Ca2+信号传导的依赖性。这项研究的结果将揭示新的机制， 宿主适应这种真菌，这将为未来的治疗策略，以增加宿主 清除机制。

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.