ER stress and calcium in host adaptation of A. fumigatus

霉菌病原体烟曲霉菌的感染仍然是有效的主要障碍。 免疫功能低下患者的处理，特别是血液系统恶性肿瘤患者的处理 移植、慢性肉芽肿性疾病或囊性纤维化。尽管我们在理解上取得了一些进步 对于这种感染，目前还不清楚这种真菌是如何如此容易地适应宿主环境并逃脱清除的。 在长期殖民的情况下。未折叠蛋白反应(UPR)是一种信号通路，它能感知 内质网(ER)上的压力负荷，并将该信息传递给细胞核。当前 证据表明，房颤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全。 明白了。这笔赠款中初步数据为普遍定期审议功能的新机制提供了证据 涉及细胞内钙离子水平的调节，以响应房颤必须适应的两种应激条件 宿主：(1)由于对分泌途径的需求增加而导致的内质网稳态的丧失；(2)直接 被先天免疫系统的细胞攻击。由于钙离子是一种强有力的第二信使，这些发现表明 UPR与将细胞质钙信号解码为宿主适应性信号的信号通路整合在一起 回应。我们提出三个目标来确定房颤适应这些应激源的机制 1将确定在内质网应激过程中，UPR如何与钙信号联系，以及它与钙调神经磷酸酶之间的关系 激活和毒力，目标2将确定先天免疫系统细胞触发的机制 钙离子进入真菌，并阐明这些事件对真菌存活的影响。最后，《目标3》将使用 一种无偏见的方法描述全基因组对中性粒细胞的转录和翻译反应 攻击，以及它们对钙信号的依赖。这项研究的结果将揭示新的机制 这种真菌对宿主的适应，这将为未来扩大宿主的治疗策略铺平道路 许可机制。

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.