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肺结核一样多。唑类药物是唯一可口服的抗霉菌剂，对这些药物的耐药性正在增加，可能是由于它们用作农业杀真菌剂。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，受癌症影响的人或需要器官移植的人都有被它引起致命感染的风险。烟曲霉菌在肺内存活，迫切需要更多关于这种病原体的基本信息，以便我们开始设计未来的治疗方法。通过询问哪些转录因子控制A.通过研究烟曲霉菌引起疾病的机制，我们可以实现对驱动感染的监管网络的全球视野。我们已经创建了一个基因组规模的401 A集合。烟曲霉条形码突变体，每个缺乏一个单一的TF。我们现在将使用具有突变体文库和最先进的DNA测序技术的鼠感染模型，以同时测试所有TF突变体的毒力。为了鉴定由致病性TF调控的基因，我们将使用ChIP-Seq分析和转录组分析（RNA-Seq）。对这些数据集的计算分析将揭示驱动A.并直接引导我们找到我们需要用新药靶向的真菌过程。

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.