Aspergillus fumigatus transcriptome sequencig: protein phosphatase PpzA is involved in iron assimilation, secondary metabolite production, and virulence. Aspergillus fumigatus strain:CEA17akuB KU80

Iron restriction imposed by mammalian hosts during an infection is a common mechanism of defense to reduce or avoid the pathogen infection. Iron is essential for organism survival due to its involvement in several biological processes. Aspergillus fumigatus causes invasive aspergillosis (IA), a disease that typically manifests in immunocompromised patients. A. fumigatus has two high affinity mechanisms of iron acquisition during infection: reductive iron assimilation (RIA) and siderophore-mediated iron uptake. It has been shown that siderophore production is important for A. fumigatus virulence, differently to the reductive iron uptake system. A. fumigatus PpzA, the catalytic subunit of protein phosphatase Z (PPZ), has been recently identified as associated with iron assimilation. Transcriptomic and proteomic comparisons between ∆ppzA and wild-type strains under iron starvation showed that PpzA has a broad influence on genes involved in secondary metabolism. LC-MS under standard and iron starvation conditions confirmed that the ΔppzA mutant had reduced production of pyripyropene A (PPA), fumagillin, fumiquinazoline A, TAFC, and helvolic acid. The ΔppzA was shown to be avirulent in a neutropenic murine model of invasive pulmonary aspergillosis. PpzA plays an important role at the interface between iron starvation, regulation of SM production and pathogenicity in A. fumigatus.

哺乳动物宿主在感染过程中实施的铁限制策略，是一类常见的防御机制，用于降低乃至完全规避病原体的感染。铁元素因参与多种生物学过程，对生物体的存活至关重要。烟曲霉（Aspergillus fumigatus）可引发侵袭性曲霉病（invasive aspergillosis, IA），该病通常在免疫功能低下的患者群体中发病。烟曲霉在感染期间具备两种高亲和力的铁获取机制：还原性铁同化（reductive iron assimilation, RIA）途径，以及铁载体（siderophore）介导的铁摄取途径。已有研究证实，与还原性铁摄取系统不同，铁载体的产生对于烟曲霉的毒力具有关键作用。近期研究发现，烟曲霉的蛋白磷酸酶Z（protein phosphatase Z, PPZ）催化亚基PpzA与铁同化过程相关联。对铁饥饿条件下的ΔppzA突变株与野生型菌株开展转录组与蛋白质组比较分析，结果显示PpzA对参与次级代谢的基因存在广泛的调控影响。在标准培养及铁饥饿条件下采用液相色谱-质谱联用（LC-MS）进行检测，证实ΔppzA突变株的吡咯并吡咯A（pyripyropene A, PPA）、烟曲霉素（fumagillin）、烟曲霉喹唑啉A（fumiquinazoline A）、三乙酰基镰孢菌素C（TAFC）以及黑曲霉酸（helvolic acid）的合成量均显著降低。研究表明，ΔppzA突变株在侵袭性肺曲霉病的中性粒细胞减少小鼠模型中完全丧失致病力。PpzA在烟曲霉的铁饥饿响应、次级代谢产物合成调控与致病性之间的调控交互界面中发挥着重要作用。