Centre for Metabolomics and Bioanalysis (CEMBIO), Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain.
Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, Rua do Matão, Travessa 14, 101, São Paulo CEP-05508-090, SP, Brazil.
Int J Mol Sci. 2021 Jun 26;22(13):6883. doi: 10.3390/ijms22136883.
survival inside macrophages depends on factors that lead to the immune response evasion during the infection. In this context, the metabolic scenario of the host cell-parasite relationship can be crucial to understanding how this parasite can survive inside host cells due to the host's metabolic pathways reprogramming. In this work, we aimed to analyze metabolic networks of bone marrow-derived macrophages from C57BL/6 mice infected with wild type (-WT) or arginase knocked out (-arg), using the untargeted Capillary Electrophoresis-Mass Spectrometry (CE-MS) approach to assess metabolomic profile. Macrophages showed specific changes in metabolite abundance upon infection, as well as in the absence of parasite-arginase. The absence of -arginase promoted the regulation of both host and parasite urea cycle, glycine and serine metabolism, ammonia recycling, metabolism of arginine, proline, aspartate, glutamate, spermidine, spermine, methylhistidine, and glutathione metabolism. The increased L-arginine, L-citrulline, L-glutamine, oxidized glutathione, S-adenosylmethionine, -acetylspermidine, trypanothione disulfide, and trypanothione levels were observed in -WT-infected C57BL/6-macrophage compared to uninfected. The absence of parasite arginase increased L-arginine, argininic acid, and citrulline levels and reduced ornithine, putrescine, S-adenosylmethionine, glutamic acid, proline, -glutamyl-alanine, glutamyl-arginine, trypanothione disulfide, and trypanothione when compared to -WT infected macrophage. Moreover, the absence of parasite arginase leads to an increase in NO production levels and a higher infectivity rate at 4 h of infection. The data presented here show a host-dependent regulation of metabolomic profiles of C57BL/6 macrophages compared to the previously observed BALB/c macrophages infected with an important fact due to the dual and contrasting macrophage phenotypes of those mice. In addition, the -arginase showed interference with the urea cycle, glycine, and glutathione metabolism during host-pathogen interactions.
在感染过程中，逃避免疫反应的因素决定了巨噬细胞内的存活。在这种情况下，宿主细胞-寄生虫关系的代谢情况对于理解寄生虫如何在宿主细胞内存活至关重要，因为宿主的代谢途径会被重新编程。在这项工作中，我们旨在使用非靶向性毛细管电泳-质谱 (CE-MS) 方法分析感染野生型 (-WT) 或精氨酸酶敲除 (-arg) 的 C57BL/6 小鼠骨髓来源的巨噬细胞的代谢网络，以评估代谢组学特征。感染后，以及在没有寄生虫精氨酸酶的情况下，巨噬细胞中的代谢物丰度表现出特定的变化。缺乏 -arg 促进了宿主和寄生虫尿素循环、甘氨酸和丝氨酸代谢、氨回收、精氨酸、脯氨酸、天冬氨酸、谷氨酸、亚精胺、精胺、甲基组氨酸和谷胱甘肽代谢的调节。与未感染相比，-WT 感染的 C57BL/6 巨噬细胞中观察到 L-精氨酸、L-瓜氨酸、L-谷氨酰胺、氧化型谷胱甘肽、S-腺苷甲硫氨酸、-乙酰亚精胺、三氮脒二硫和三氮脒的水平升高。与 -WT 感染的巨噬细胞相比，寄生虫精氨酸酶的缺失增加了 L-精氨酸、精氨酸酸和瓜氨酸的水平，降低了鸟氨酸、腐胺、S-腺苷甲硫氨酸、谷氨酸、脯氨酸、-谷氨酰-丙氨酸、谷氨酰-精氨酸、三氮脒二硫和三氮脒。此外，寄生虫精氨酸酶的缺失导致感染后 4 小时 NO 产生水平升高和感染率增加。与之前观察到的 BALB/c 巨噬细胞感染相比，这里呈现的数据显示了 C57BL/6 巨噬细胞的代谢组学图谱受宿主依赖性调节，这是一个重要的事实，因为这些小鼠的巨噬细胞具有双重和对比鲜明的表型。此外，精氨酸酶在宿主-病原体相互作用过程中干扰了尿素循环、甘氨酸和谷胱甘肽代谢。
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