The F(1)F(o)-ATP synthase α subunit of Candida albicans induces inflammatory responses by controlling amino acid catabolism.
The F(1)F(o)-ATP synthase α subunit of Candida albicans induces inflammatory responses by controlling amino acid catabolism.
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DOI：
10.1080/21505594.2023.2190645
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发表时间：
2023-12
期刊：
影响因子：
5.2
通讯作者：
Zhang, Hong
中科院分区：
文献类型：
--
作者：
Li, Shuixiu;Liu, Yuting;Weng, Luobei;Zhao, Yajing;Zhang, Yishan;Zhang, Zhanpeng;Yang, Yang;Chen, Qiaoxin;Liu, Xiaocong;Zhang, Hong
脓毒症是侵袭性念珠菌病致死的主要原因。炎症反应的程度是脓毒症结局的决定因素，并且炎症细胞因子失衡是病理生理过程的中心。我们以前证明了白色念珠菌F1 Fo-ATP合酶α亚基缺失突变体对小鼠是非致死性的。本文主要研究F1 Fo-ATP合酶α亚基在宿主炎症反应中的作用及其机制。与野生型菌株相比，F1 Fo-ATP合成酶α亚基缺失突变体在大蜡螟和小鼠系统性念珠菌病模型中不能诱导炎症反应，并且显著降低了肾脏中促炎细胞因子IL-1β、IL-6的mRNA水平，增加了抗炎细胞因子IL-4的mRNA水平。在C.在白念珠菌-巨噬细胞共培养中，F1 Fo-ATP合酶α亚基缺失突变体以酵母形式被捕获在巨噬细胞内，并且其活化（诱导炎症反应的关键因子）被抑制。在模拟巨噬细胞的微环境中，F1 Fo-ATP合成酶α亚基缺失突变体阻断了微丝调节的核心途径cAMP/PKA途径，因为它不能通过分解代谢巨噬细胞内重要的替代碳源氨基酸来碱化环境。突变体下调Put 1和Put 2，两个必需的氨基酸分解代谢酶，可能是由于严重受损的氧化磷酸化。我们的研究结果表明，C。白念珠菌F1 Fo-ATP合酶α亚基通过调控自身氨基酸催化剂来诱导宿主炎症反应，寻找抑制F1 Fo-ATP合酶α亚基活性的药物对控制宿主炎症反应的诱导具有重要意义。
Sepsis is a leading cause of fatality in invasive candidiasis. The magnitude of the inflammatory response is a determinant of sepsis outcomes, and inflammatory cytokine imbalances are central to the pathophysiological processes. We previously demonstrated that a Candida albicans F1Fo-ATP synthase α subunit deletion mutant was nonlethal to mice. Here, the potential effects of the F1Fo-ATP synthase α subunit on host inflammatory responses and the mechanism were studied. Compared with wild-type strain, the F1Fo-ATP synthase α subunit deletion mutant failed to induce inflammatory responses in Galleria mellonella and murine systemic candidiasis models and significantly decreased the mRNA levels of the proinflammatory cytokines IL-1β, IL-6 and increased those of the anti-inflammatory cytokine IL-4 in the kidney. During C. albicans-macrophage co-culture, the F1Fo-ATP synthase α subunit deletion mutant was trapped inside macrophages in yeast form, and its filamentation, a key factor in inducing inflammatory responses, was inhibited. In the macrophage-mimicking microenvironment, the F1Fo-ATP synthase α subunit deletion mutant blocked the cAMP/PKA pathway, the core filamentation-regulating pathway, because it failed to alkalinize environment by catabolizing amino acids, an important alternative carbon source inside macrophages. The mutant downregulated Put1 and Put2, two essential amino acid catabolic enzymes, possibly due to severely impaired oxidative phosphorylation. Our findings reveal that the C. albicans F1Fo-ATP synthase α subunit induces host inflammatory responses by controlling its own amino acid catabolism and it is significant to find drugs that inhibit F1Fo-ATP synthase α subunit activity to control the induction of host inflammatory responses.
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影响因子：
7.3
作者：
Horiguchi H;Loftus TJ;Hawkins RB;Raymond SL;Stortz JA;Hollen MK;Weiss BP;Miller ES;Bihorac A;Larson SD;Mohr AM;Brakenridge SC;Tsujimoto H;Ueno H;Moore FA;Moldawer LL;Efron PA;Sepsis and Critical Illness Research Center Investigators
通讯作者：
Sepsis and Critical Illness Research Center Investigators
影响因子：
16.6
作者：
Ding X;Kambara H;Guo R;Kanneganti A;Acosta-Zaldívar M;Li J;Liu F;Bei T;Qi W;Xie X;Han W;Liu N;Zhang C;Zhang X;Yu H;Zhao L;Ma F;Köhler JR;Luo HR
通讯作者：
Luo HR
影响因子：
16.6
作者：
Kasper L;König A;Koenig PA;Gresnigt MS;Westman J;Drummond RA;Lionakis MS;Groß O;Ruland J;Naglik JR;Hube B
通讯作者：
Hube B
影响因子：
7.3
作者：
Ferreira-Gomes M;Wich M;Böde S;Hube B;Jacobsen ID;Jungnickel B
通讯作者：
Jungnickel B
影响因子：
5.2
作者：
Garbe, Enrico;Vylkova, Slavena
通讯作者：
Vylkova, Slavena