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Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis.
PLOS Neglected Tropical Diseases ( IF 3.4 ) Pub Date : 2020-03-26 , DOI: 10.1371/journal.pntd.0008125 Carolina Ferreira 1, 2 , Inês Mesquita 1, 2 , Ana Margarida Barbosa 1, 2 , Nuno Sampaio Osório 1, 2 , Egídio Torrado 1, 2 , Charles-Joly Beauparlant 3, 4 , Arnaud Droit 3, 4 , Cristina Cunha 1, 2 , Agostinho Carvalho 1, 2 , Bhaskar Saha 5, 6 , Jerôme Estaquier 4, 7 , Ricardo Silvestre 1, 2
PLOS Neglected Tropical Diseases ( IF 3.4 ) Pub Date : 2020-03-26 , DOI: 10.1371/journal.pntd.0008125 Carolina Ferreira 1, 2 , Inês Mesquita 1, 2 , Ana Margarida Barbosa 1, 2 , Nuno Sampaio Osório 1, 2 , Egídio Torrado 1, 2 , Charles-Joly Beauparlant 3, 4 , Arnaud Droit 3, 4 , Cristina Cunha 1, 2 , Agostinho Carvalho 1, 2 , Bhaskar Saha 5, 6 , Jerôme Estaquier 4, 7 , Ricardo Silvestre 1, 2
Affiliation
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BACKGROUND
The disturbance of host metabolic pathways by Leishmania parasites has crucial consequences for the activation status of immune cells and the outcome of infection. Glutamine has been described as an immunomodulatory amino acid, yet its role during Leishmania infection is still unknown.
METHODS
We performed transcriptomics in uninfected and L. donovani-infected macrophages 6 hours post-infection. Glutamine quantification by HPLC was assessed in the supernatant of macrophages throughout the infection course. For experimental L. donovani infections, mice were infected with 1.0 x 108 stationary L. donovani promastigotes. Glutaminase (GLS) chemical inhibition was performed using BPTES and glutamine was administered throughout infection. For combined therapy experiment, a daily administration of miltefosine and glutamine was performed by oral gavage. Parasite burden was determined using a Taqman-based assay. Immune cell phenotyping and cytotoxicity were performed in splenic cells using flow cytometry.
FINDINGS
We show that glutamine is essential for the control of L. donovani infection. Transcriptomic analysis of L. donovani-infected macrophages demonstrated an upregulation of genes involved in glutamine metabolism. Pharmacological inhibition of glutaminolysis significantly increased the susceptibility to infection, accompanied by an increased recruitment of anti-inflammatory myeloid cells and impaired T cell responses. Remarkably, the supplementation of glutamine to mice infected with L. donovani during miltefosine treatment potentiates parasite clearance through the development of a more effective anti-Leishmania adaptive immune response.
CONCLUSIONS
Our data indicates that dietary glutamine supplementation may act as a promising adjuvant for the treatment of visceral leishmaniasis.
中文翻译：
补充谷氨酰胺可改善米替福辛治疗内脏利什曼病的功效。
背景技术利什曼原虫寄生虫对宿主代谢途径的干扰对免疫细胞的活化状态和感染的结果具有至关重要的影响。谷氨酰胺已被描述为一种免疫调节氨基酸，但其在利什曼原虫感染中的作用仍是未知的。方法我们在感染后6小时对未感染和经多巴尼酵母感染的巨噬细胞进行了转录组学研究。在整个感染过程中，在巨噬细胞的上清液中通过HPLC对谷氨酰胺定量。对于实验性多诺氏乳杆菌感染，用1.0×108个固定的多诺氏乳杆菌前鞭毛体感染小鼠。使用BPTES对谷氨酰胺酶（GLS）进行化学抑制，并在整个感染过程中给予谷氨酰胺。对于联合疗法实验，每天通过管饲法给予米替福星和谷氨酰胺。使用基于Taqman的测定法确定寄生虫负担。使用流式细胞术在脾细胞中进行免疫细胞表型和细胞毒性。结果我们表明，谷氨酰胺对于控制多诺氏乳杆菌感染至关重要。感染多诺曼氏菌的巨噬细胞的转录组学分析表明，涉及谷氨酰胺代谢的基因上调。谷氨酰胺分解的药理学抑制作用显着增加了对感染的敏感性，同时增加了抗炎性髓细胞的募集和T细胞反应的减弱。值得注意的是，谷氨酰胺对感染L的小鼠的补充。多诺芬在米替福辛治疗期间通过开发更有效的抗利什曼原虫适应性免疫应答来增强寄生虫清除。结论我们的数据表明，膳食谷氨酰胺补充剂可作为内脏利什曼病的有前途的佐剂。
更新日期：2020-03-27
中文翻译：
补充谷氨酰胺可改善米替福辛治疗内脏利什曼病的功效。
背景技术利什曼原虫寄生虫对宿主代谢途径的干扰对免疫细胞的活化状态和感染的结果具有至关重要的影响。谷氨酰胺已被描述为一种免疫调节氨基酸，但其在利什曼原虫感染中的作用仍是未知的。方法我们在感染后6小时对未感染和经多巴尼酵母感染的巨噬细胞进行了转录组学研究。在整个感染过程中，在巨噬细胞的上清液中通过HPLC对谷氨酰胺定量。对于实验性多诺氏乳杆菌感染，用1.0×108个固定的多诺氏乳杆菌前鞭毛体感染小鼠。使用BPTES对谷氨酰胺酶（GLS）进行化学抑制，并在整个感染过程中给予谷氨酰胺。对于联合疗法实验，每天通过管饲法给予米替福星和谷氨酰胺。使用基于Taqman的测定法确定寄生虫负担。使用流式细胞术在脾细胞中进行免疫细胞表型和细胞毒性。结果我们表明，谷氨酰胺对于控制多诺氏乳杆菌感染至关重要。感染多诺曼氏菌的巨噬细胞的转录组学分析表明，涉及谷氨酰胺代谢的基因上调。谷氨酰胺分解的药理学抑制作用显着增加了对感染的敏感性，同时增加了抗炎性髓细胞的募集和T细胞反应的减弱。值得注意的是，谷氨酰胺对感染L的小鼠的补充。多诺芬在米替福辛治疗期间通过开发更有效的抗利什曼原虫适应性免疫应答来增强寄生虫清除。结论我们的数据表明，膳食谷氨酰胺补充剂可作为内脏利什曼病的有前途的佐剂。
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