McDonagh Andrew, Fedorova Natalie D, Crabtree Jonathan, Yu Yan, Kim Stanley, Chen Dan, Loss Omar, Cairns Timothy, Goldman Gustavo, Armstrong-James Darius, Haynes Ken, Haas Hubertus, Schrettl Markus, May Gregory, Nierman William C, Bignell Elaine
Department of Microbiology, Imperial College London, London, United Kingdom.
PLoS Pathog. 2008 Sep 12;4(9):e1000154. doi: 10.1371/journal.ppat.1000154.
Aspergillus fumigatus is a common mould whose spores are a component of the normal airborne flora. Immune dysfunction permits developmental growth of inhaled spores in the human lung causing aspergillosis, a significant threat to human health in the form of allergic, and life-threatening invasive infections. The success of A. fumigatus as a pathogen is unique among close phylogenetic relatives and is poorly characterised at the molecular level. Recent genome sequencing of several Aspergillus species provides an exceptional opportunity to analyse fungal virulence attributes within a genomic and evolutionary context. To identify genes preferentially expressed during adaptation to the mammalian host niche, we generated multiple gene expression profiles from minute samplings of A. fumigatus germlings during initiation of murine infection. They reveal a highly co-ordinated A. fumigatus gene expression programme, governing metabolic and physiological adaptation, which allows the organism to prosper within the mammalian niche. As functions of phylogenetic conservation and genetic locus, 28% and 30%, respectively, of the A. fumigatus subtelomeric and lineage-specific gene repertoires are induced relative to laboratory culture, and physically clustered genes including loci directing pseurotin, gliotoxin and siderophore biosyntheses are a prominent feature. Locationally biased A. fumigatus gene expression is not prompted by in vitro iron limitation, acid, alkaline, anaerobic or oxidative stress. However, subtelomeric gene expression is favoured following ex vivo neutrophil exposure and in comparative analyses of richly and poorly nourished laboratory cultured germlings. We found remarkable concordance between the A. fumigatus host-adaptation transcriptome and those resulting from in vitro iron depletion, alkaline shift, nitrogen starvation and loss of the methyltransferase LaeA. This first transcriptional snapshot of a fungal genome during initiation of mammalian infection provides the global perspective required to direct much-needed diagnostic and therapeutic strategies and reveals genome organisation and subtelomeric diversity as potential driving forces in the evolution of pathogenicity in the genus Aspergillus.
烟曲霉是一种常见霉菌，其孢子是正常空气微生物群落的组成部分。免疫功能障碍会使吸入肺部的孢子在人体肺部发育生长，从而引发曲霉病，这是一种以过敏和危及生命的侵袭性感染形式对人类健康构成重大威胁的疾病。烟曲霉作为一种病原体，在其近缘系统发育亲属中表现独特，在分子水平上的特征了解甚少。最近对几种曲霉属物种进行的基因组测序提供了一个绝佳机会，可在基因组和进化背景下分析真菌的毒力属性。为了鉴定在适应哺乳动物宿主生态位过程中优先表达的基因，我们在小鼠感染初期对烟曲霉芽孢进行微量采样，生成了多个基因表达谱。这些表达谱揭示了一个高度协调的烟曲霉基因表达程序，该程序控制着代谢和生理适应过程，使该生物体能够在哺乳动物生态位中茁壮成长。作为系统发育保守性和基因座功能的体现，相对于实验室培养条件，烟曲霉端粒附近和谱系特异性基因库中分别有28%和30%的基因被诱导表达，包括指导假丝菌素、胶霉毒素和铁载体生物合成的基因座在内的物理聚集基因是一个显著特征。烟曲霉基因表达的位置偏向性并非由体外铁限制、酸、碱、厌氧或氧化应激所引发。然而，离体中性粒细胞暴露后以及在营养丰富和营养匮乏的实验室培养芽孢的比较分析中，端粒附近基因的表达更受青睐。我们发现烟曲霉宿主适应转录组与体外缺铁、碱性转变、氮饥饿以及甲基转移酶LaeA缺失所产生的转录组之间存在显著一致性。这一首次在哺乳动物感染初期对真菌基因组进行的转录快照提供了指导急需的诊断和治疗策略所需的全局视角，并揭示了基因组组织和端粒附近多样性是曲霉属致病性进化中的潜在驱动力。
