Pongpom Monsicha, Liu Hong, Xu Wenjie, Snarr Brendan D, Sheppard Donald C, Mitchell Aaron P, Filler Scott G
Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
Infect Immun. 2015 Mar;83(3):923-33. doi: 10.1128/IAI.02685-14. Epub 2014 Dec 22.
In Aspergillus nidulans, the AcuK and AcuM transcription factors form a complex that regulates gluconeogenesis. In Aspergillus fumigatus, AcuM governs gluconeogenesis and iron acquisition in vitro and virulence in immunosuppressed mice. However, the function of AcuK was previously unknown. Through in vitro studies, we found that A. fumigatus ΔacuK single and ΔacuK ΔacuM double mutants had impaired gluconeogenesis and iron acquisition, similar to the ΔacuM mutant. Also, the ΔacuK, ΔacuM, and ΔacuK ΔacuM mutants had similar virulence defects in mice. However, the ΔacuK mutant had a milder defect in extracellular siderophore activity and induction of epithelial cell damage in vitro than did the ΔacuM mutant. Moreover, overexpression of acuM in the ΔacuK mutant altered expression of 3 genes and partially restored growth under iron-limited conditions, suggesting that AcuM can govern some genes independently of AcuK. Although the ΔacuK and ΔacuM mutants had very similar transcriptional profiles in vitro, their transcriptional profiles during murine pulmonary infection differed both from their in vitro profiles and from each other. While AcuK and AcuM governed the expression of only a few iron-responsive genes in vivo, they influenced the expression of other virulence-related genes, such as hexA and dvrA. Therefore, in A. fumigatus, while AcuK and AcuM likely function as part of the same complex, they can also function independently of each other. Furthermore, AcuK and AcuM have different target genes in vivo than in vitro, suggesting that in vivo infection stimulates unique transcriptional regulatory pathways in A. fumigatus.
在构巢曲霉中，AcuK和AcuM转录因子形成一个调控糖异生的复合体。在烟曲霉中，AcuM在体外调控糖异生和铁摄取，并在免疫抑制小鼠中影响毒力。然而，AcuK的功能此前尚不清楚。通过体外研究，我们发现烟曲霉ΔacuK单突变体和ΔacuK ΔacuM双突变体的糖异生和铁摄取受损，与ΔacuM突变体相似。此外，ΔacuK、ΔacuM和ΔacuK ΔacuM突变体在小鼠中具有相似的毒力缺陷。然而，ΔacuK突变体在细胞外铁载体活性和体外诱导上皮细胞损伤方面的缺陷比ΔacuM突变体更轻微。此外，在ΔacuK突变体中过表达acuM改变了3个基因的表达，并在铁限制条件下部分恢复了生长，这表明AcuM可以独立于AcuK调控一些基因。虽然ΔacuK和ΔacuM突变体在体外具有非常相似的转录谱，但它们在小鼠肺部感染期间的转录谱与体外谱不同，且彼此也不同。虽然AcuK和AcuM在体内仅调控少数铁反应基因的表达，但它们影响其他毒力相关基因的表达，如hexA和dvrA。因此，在烟曲霉中，虽然AcuK和AcuM可能作为同一复合体的一部分发挥作用，但它们也可以彼此独立发挥作用。此外，AcuK和AcuM在体内的靶基因与体外不同，这表明体内感染刺激了烟曲霉独特的转录调控途径。
