Pradhan Arnab, Herrero-de-Dios Carmen, Belmonte Rodrigo, Budge Susan, Lopez Garcia Angela, Kolmogorova Aljona, Lee Keunsook K, Martin Brennan D, Ribeiro Antonio, Bebes Attila, Yuecel Raif, Gow Neil A R, Munro Carol A, MacCallum Donna M, Quinn Janet, Brown Alistair J P
Aberdeen Fungal Group, MRC Centre for Medical Mycology, University of Aberdeen, Institute of Medical Sciences, Aberdeen, United Kingdom.
Centre for Genome-Enabled Biology and Medicine, University of Aberdeen, Aberdeen, United Kingdom.
PLoS Pathog. 2017 May 22;13(5):e1006405. doi: 10.1371/journal.ppat.1006405. eCollection 2017 May.
Most fungal pathogens of humans display robust protective oxidative stress responses that contribute to their pathogenicity. The induction of enzymes that detoxify reactive oxygen species (ROS) is an essential component of these responses. We showed previously that ectopic expression of the heme-containing catalase enzyme in Candida albicans enhances resistance to oxidative stress, combinatorial oxidative plus cationic stress, and phagocytic killing. Clearly ectopic catalase expression confers fitness advantages in the presence of stress, and therefore in this study we tested whether it enhances fitness in the absence of stress. We addressed this using a set of congenic barcoded C. albicans strains that include doxycycline-conditional tetON-CAT1 expressors. We show that high basal catalase levels, rather than CAT1 induction following stress imposition, reduce ROS accumulation and cell death, thereby promoting resistance to acute peroxide or combinatorial stress. This conclusion is reinforced by our analyses of phenotypically diverse clinical isolates and the impact of stochastic variation in catalase expression upon stress resistance in genetically homogeneous C. albicans populations. Accordingly, cat1Δ cells are more sensitive to neutrophil killing. However, we find that catalase inactivation does not attenuate C. albicans virulence in mouse or invertebrate models of systemic candidiasis. Furthermore, our direct comparisons of fitness in vitro using isogenic barcoded CAT1, cat1Δ and tetON-CAT1 strains show that, while ectopic catalase expression confers a fitness advantage during peroxide stress, it confers a fitness defect in the absence of stress. This fitness defect is suppressed by iron supplementation. Also high basal catalase levels induce key iron assimilatory functions (CFL5, FET3, FRP1, FTR1). We conclude that while high basal catalase levels enhance peroxide stress resistance, they place pressure on iron homeostasis through an elevated cellular demand for iron, thereby reducing the fitness of C. albicans in iron-limiting tissues within the host.
大多数人类真菌病原体表现出强大的保护性氧化应激反应，这有助于它们的致病性。诱导解毒活性氧（ROS）的酶是这些反应的重要组成部分。我们之前表明，在白色念珠菌中异位表达含血红素的过氧化氢酶可增强对氧化应激、氧化加阳离子应激和吞噬杀伤的抗性。显然，异位过氧化氢酶表达在应激存在时赋予了适应性优势，因此在本研究中，我们测试了它在无应激情况下是否能增强适应性。我们使用一组同基因条形码白色念珠菌菌株来解决这个问题，这些菌株包括强力霉素条件性tetON - CAT1表达菌株。我们表明，高基础过氧化氢酶水平，而非应激施加后的CAT1诱导，可减少ROS积累和细胞死亡，从而增强对急性过氧化物或复合应激的抗性。我们对表型多样的临床分离株的分析以及过氧化氢酶表达的随机变化对基因同质的白色念珠菌群体应激抗性的影响，强化了这一结论。因此，cat1Δ细胞对中性粒细胞杀伤更敏感。然而，我们发现过氧化氢酶失活并不会减弱白色念珠菌在系统性念珠菌病的小鼠或无脊椎动物模型中的毒力。此外，我们使用同基因条形码CAT1、cat1Δ和tetON - CAT1菌株在体外直接比较适应性，结果表明，虽然异位过氧化氢酶表达在过氧化物应激期间赋予适应性优势，但在无应激情况下却赋予适应性缺陷。这种适应性缺陷可通过补充铁来抑制。高基础过氧化氢酶水平还诱导关键的铁同化功能（CFL5、FET3、FRP1、FTR1）。我们得出结论，虽然高基础过氧化氢酶水平增强了对过氧化物应激的抗性，但它们通过细胞对铁的需求增加对铁稳态施加压力，从而降低了白色念珠菌在宿主内铁限制组织中的适应性。
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