Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
ICVS/3B's-PT Government Associate Laboratory, Guimarães/Braga, Portugal.
Microbiol Spectr. 2023 Feb 14;11(1):e0225622. doi: 10.1128/spectrum.02256-22. Epub 2022 Dec 8.
The reprogramming of cellular metabolism of immune cells is an essential process in the regulation of antifungal immune responses. In particular, glucose metabolism has been shown to be required for protective immunity against infection with Aspergillus fumigatus. However, given the intricate cross talk between multiple metabolic networks and signals, it is likely that cellular metabolic pathways other than glycolysis are also relevant during fungal infection. In this study, we demonstrate that glutamine metabolism is required for the activation of macrophage effector functions against A. fumigatus. Glutamine metabolism was found to be upregulated early after fungal infection and glutamine depletion or the pharmacological inhibition of enzymes involved in its metabolism impaired phagocytosis and the production of both proinflammatory and T-cell-derived cytokines. In an model, inhibition of glutaminase increased susceptibility to experimental aspergillosis, as revealed by the increased fungal burden and inflammatory pathology, and the defective cytokine production in the lungs. Moreover, genetic variants in glutamine metabolism genes were found to regulate cytokine production in response to A. fumigatus stimulation. Taken together, our results demonstrate that glutamine metabolism represents an important component of the immunometabolic response of macrophages against A. fumigatus both and . The fungal pathogen Aspergillus fumigatus can cause severe and life-threatening forms of infection in immunocompromised patients. The reprogramming of cellular metabolism is essential for innate immune cells to mount effective antifungal responses. In this study, we report the pivotal contribution of glutaminolysis to the host defense against A. fumigatus. Glutamine metabolism was essential both as well as in models of infection, and genetic variants in human glutamine metabolism genes regulated cytokine production in response to fungal stimulation. This work highlights the relevance of glutaminolysis to the pathogenesis of aspergillosis and supports a role for interindividual genetic variation influencing glutamine metabolism in susceptibility to infection.
细胞代谢的重编程是调节抗真菌免疫反应的一个重要过程。特别是，葡萄糖代谢已被证明是对抗烟曲霉感染的保护性免疫所必需的。然而，鉴于多个代谢网络和信号之间的复杂相互作用，细胞代谢途径除了糖酵解之外，在真菌感染过程中也可能具有相关性。在这项研究中，我们证明了谷氨酰胺代谢对于巨噬细胞对抗烟曲霉的效应功能的激活是必需的。研究发现，真菌感染后早期谷氨酰胺代谢上调，谷氨酰胺耗竭或其代谢相关酶的药理学抑制会损害吞噬作用以及促炎细胞因子和 T 细胞衍生细胞因子的产生。在一个 模型中，谷氨酰胺酶的抑制增加了对实验性曲霉病的易感性，这表现在肺部真菌负荷和炎症病理学增加，以及细胞因子产生缺陷。此外，谷氨酰胺代谢基因的遗传变异被发现可调节对烟曲霉刺激的细胞因子产生。总之，我们的研究结果表明，谷氨酰胺代谢代表了巨噬细胞对烟曲霉的免疫代谢反应的一个重要组成部分。烟曲霉病原体可导致免疫功能低下患者发生严重和危及生命的感染形式。细胞代谢的重编程对于先天免疫细胞产生有效的抗真菌反应是必不可少的。在这项研究中，我们报告了谷氨酰胺分解代谢对宿主防御烟曲霉的关键贡献。谷氨酰胺代谢在感染的 模型中是必需的，人类谷氨酰胺代谢基因的遗传变异调节了对真菌刺激的细胞因子产生。这项工作强调了谷氨酰胺分解代谢与曲霉病发病机制的相关性，并支持个体间遗传变异影响感染易感性的作用。
