The Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, China.
Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou Central Hospital, Huzhou Universitygrid.411440.4, Huzhou, Zhejiang, China.
Microbiol Spectr. 2022 Feb 23;10(1):e0199921. doi: 10.1128/spectrum.01999-21.
A human host exploits stresses such as acidic/alkaline pH, antifungal drugs, and reactive oxygen species to kill microbial pathogens such as the fungus Aspergillus fumigatus. However, A. fumigatus is resistant to these stresses . Therefore, what accounts for the potent antifungal activity of the human host? In this observation, we show that simultaneous exposure to acidic pH and oxidative stresses is much more potent than the individual stresses themselves and that this combinatorial stress kills A. fumigatus synergistically . Interestingly, A. fumigatus is resistant to the combination of alkaline pH and oxidative stress. Quantitative real-time PCR analyses showed that acidic/alkaline pH stress can mediate oxidative stress responses in A. fumigatus by regulating the expression of catalase-encoding genes. We further show that A. fumigatus is sensitive to the combination of acidic/alkaline stress and azole drug stress. Transcriptome analysis revealed that the sensitivity of A. fumigatus to azole drugs under acidic/alkaline conditions may be related to changes in genetic stability, sphingolipid metabolism, lipid metabolism, and amino acid metabolism. Collectively, our findings suggest that combinatorial stress represents a powerful fungicidal mechanism employed by hosts against pathogens, which suggests novel approaches to potentiate antifungal therapy. The human host combats fungal infections via phagocytic cells that recognize and kill fungal pathogens. Immune cells combat Aspergillus fumigatus infections with a potent mixture of chemicals, including reactive oxygen species, acidic/alkaline stress, and antifungal drugs. However, A. fumigatus is relatively resistant to these stresses . In this observation, we show that it is the combination of acidic/alkaline pH and oxidative or azole stress that kills A. fumigatus so effectively, and we define the molecular mechanisms that underlie this potency. Our findings suggest that combinatorial stress is a powerful fungicidal mechanism employed by hosts, which suggests novel approaches to potentiate antifungal therapy. This study provides a platform for future studies that will address the combinatorial impacts of various environmental stresses on A. fumigatus and other pathogenic microbes.
人类宿主利用酸性/碱性 pH 值、抗真菌药物和活性氧等应激因素来杀死微生物病原体，如真菌烟曲霉。然而，烟曲霉对这些应激因素具有抗性。那么，人类宿主强大的抗真菌活性是由什么决定的呢？在本观察中，我们表明，同时暴露于酸性 pH 值和氧化应激下比单独的应激因素本身更有效，并且这种组合应激协同杀死烟曲霉。有趣的是，烟曲霉对碱性 pH 值和氧化应激的组合具有抗性。定量实时 PCR 分析表明，酸性/碱性 pH 值应激可以通过调节过氧化氢酶编码基因的表达来介导烟曲霉中的氧化应激反应。我们进一步表明，烟曲霉对酸性/碱性应激和唑类药物应激的组合敏感。转录组分析表明，在酸性/碱性条件下烟曲霉对唑类药物的敏感性可能与遗传稳定性、鞘脂代谢、脂质代谢和氨基酸代谢的变化有关。总之，我们的研究结果表明，组合应激代表了宿主对抗病原体的一种强大的杀菌机制，提示了增强抗真菌治疗的新方法。 宿主通过吞噬细胞来对抗真菌感染，吞噬细胞识别并杀死真菌病原体。免疫细胞通过包括活性氧、酸性/碱性应激和抗真菌药物在内的强效化学混合物来对抗烟曲霉感染。然而，烟曲霉对这些应激因素相对具有抗性。在本观察中，我们表明正是酸性/碱性 pH 值与氧化或唑类药物应激的组合有效地杀死了烟曲霉，并定义了这种效力的分子机制。我们的研究结果表明，组合应激是宿主使用的一种强大的杀菌机制，提示了增强抗真菌治疗的新方法。这项研究为未来的研究提供了一个平台，这些研究将探讨各种环境应激因素对烟曲霉和其他致病微生物的组合影响。
