Functional roles of ncRNA afu-182 in azole response and pathobiology of Aspergillus fumigatus

项目总结： 由烟曲霉菌引起的侵袭性肺曲霉病(IPA)是一种主要的发病率和致病因素。 尽管有抗真菌药物，但免疫受损患者的死亡率。全球范围内出现的 唑类耐药是导致疾病转归较差的主要因素； 烟熏菌分离株仅占感染的5%左右。知识上的一个主要差距是对唑类的敏感程度 分离株耐受唑类药物，导致死亡率超过50%的疾病结局不佳。至 为此，我们已经鉴定出一种未鉴定的长非编码RNA(LncRNA)Afu-182，它具有负性 与唑类药物反应相关，并在实验室和临床上是唑类药物耐受性的驱动因素 分离株。在这个提案中，我们将使用基因组学、遗传学、生化方法来定义 AFU-182介导唑类药物在烟曲霉菌中的耐药在具体目标1)中，我们将定义路径 调节唑耐受性和AFU-182调节子以了解唑类药物的分子机制 宽容。在目的2)，我们将确定在活体内的AFU-182的表达，在唑类应激下，在一个小鼠模型 侵袭性肺曲霉菌病。成功完成拟议的目标具有巨大的潜力 通过确定与唑类耐药有关的机制和解密二元组来改善临床结果 真菌分离株的抗性/敏感谱。这将有助于设计更好的唑类治疗策略。 易受感染，以实现更好的疾病结果。

Project Summary: Invasive pulmonary aspergillosis (IPA) caused by Aspergillus fumigatus is a major cause of morbidity and mortality in immune-compromised patients despite the availability of antifungal drugs. The global emergence of azole drug resistance is a major factor contributing to poor disease outcomes; however, azole drug-resistant A. fumigatus isolates contribute to only about 5% of infections. A major gap in knowledge is how azole sensitive isolates tolerate azole drugs and contribute to poor disease outcomes with mortality rates in excess of 50%. To this end, we have identified an uncharacterized long non-coding RNA (lncRNA) afu-182 that negatively correlates with azole drug response and is a driver of azole drug tolerance in the laboratory and clinical isolates. In this proposal, we will use genomics, genetics, biochemical approaches to define the mechanism of afu-182 mediated azole drug tolerance in A. fumigatus. In specific Aim 1), we will define the pathways regulating azole tolerance and afu-182 regulon to understand the molecular mechanisms involved in azole tolerance. In Aim 2), we will define the afu-182 expression in vivo under azole stress in a murine model of invasive pulmonary aspergillosis. Successful completion of proposed aims has tremendous potential to improve clinical outcomes by defining mechanisms involved in azole tolerance and declassifying binary resistant/susceptible spectrum for fungal isolates. This will help design better treatment strategies for azole susceptible infections to achieve better disease outcomes.