A genome scale census of virulence factors in the major mould pathogen of human lungs, Aspergillus fumigatus

由真菌引起的传染病是一个世界性的问题，造成的死亡人数与疟疾和结核病一样多。唑类药物是唯一可口服的抗霉菌药物，对这些药物的抗药性正在增加，可能是因为它们被用作农业杀菌剂。因此，迫切需要开发新的抗真菌治疗方法。我们呼吸的空气中的主要真菌病原体被称为I，患有癌症或需要器官移植的人面临着由它引起致命感染的风险。我们还不完全了解烟曲霉菌是如何在肺内存活的，迫切需要关于这种病原体的更多基本信息，以便我们能够开始设计未来的治疗方法。通过询问哪些转录因子(TF)控制烟曲霉菌致病的能力，我们可以获得驱动感染的调控网络的全球视角。我们已经创建了401个烟曲霉条形码突变体的基因组规模的集合，每个突变体都缺少一个转铁蛋白。我们现在将使用突变体库和最先进的DNA测序技术建立小鼠感染模型，同时测试所有TF突变体的毒力。为了确定受致病因子调控的基因，我们将使用芯片序列分析和转录组图谱(RNA-Seq)。对这些数据集的计算分析将揭示驱动烟曲霉致病性的调控网络，并直接引导我们进入我们需要用新药靶标的真菌过程。

Infectious diseases caused by fungi are a worldwide problem causing as many deaths as malaria and tuberculosis. Azole drugs are the only orally available anti-mould agents and resistance to these drugs is increasing, possibly due to their use as agricultural fungicides. There is therefore a desperate need to develop new antifungal treatments. The major fungal pathogen in the air we breathe is called I and people affected by cancer, or requiring organ transplants, are at risk of fatal infections caused by it. We do not fully understand how A. fumigtaus survives inside the lung and urgently need more basic information about this pathogen so we can begin to design future therapies. By asking which transcription factors (TFs) control the ability of A. fumigatus to cause disease, we can achieve a global view of the regulatory network which drives infection. We have created a genome-scale collection of 401 A. fumigatus bar-coded mutants, each lacking a single TF. We will now use murine infection models with the mutant library and a state of the art DNA sequencing technology, to test the virulence of all TF mutants simultaneously. To identify the genes which are regulated by pathogenicity TFs we will use ChIP-Seq analysis and transcriptome profiling (RNA-Seq). Computational analyses of these datasets will reveal the regulatory network driving pathogenicity in A. fumigatus and lead us directly to the fungal processes we need to target with new drugs.