Cabezas-Cruz Alejandro, Espinosa Pedro J, Obregón Dasiel A, Alberdi Pilar, de la Fuente José
Biologie Moléculaire et Immunologie Parasitaires (BIPAR), Unité Mixte de Recherche (UMR), Institut National Recherche Agronomique, Agence Nationale Sécurité Sanitaire Alimentaire Nationale (ANSES), Ecole Nationale Vétérinaire d'Alfort, Université Paris-EstMaisons-Alfort, France.
Department of Parasitology, Faculty of Science, University of South BohemiaČeské Budějovice, Czechia.
Front Cell Infect Microbiol. 2017 Aug 17;7:375. doi: 10.3389/fcimb.2017.00375. eCollection 2017.
The obligate intracellular pathogen, , is the causative agent of life-threatening diseases in humans and animals. is an emerging tick-borne pathogen in the United States, Europe, Africa and Asia, with increasing numbers of infected people and animals every year. It is increasingly recognized that intracellular pathogens modify host cell metabolic pathways to increase infection and transmission in both vertebrate and invertebrate hosts. Recent reports have shown that amino acids are central to the host-pathogen metabolic interaction. In this study, a genome-wide search for components of amino acid metabolic pathways was performed in , the main tick vector of in the United States, for which the genome was recently published. The enzymes involved in the synthesis and degradation pathways of the twenty amino acids were identified. Then, the available transcriptomics and proteomics data was used to characterize the mRNA and protein levels of amino acid metabolic pathway components in response to infection of tick tissues and ISE6 tick cells. Our analysis was focused on the interplay between carbohydrate and amino acid metabolism during infection in ISE6 cells. The results showed that tick cells increase the synthesis of phosphoenolpyruvate (PEP) from tyrosine to control infection. Metabolic pathway analysis suggested that this is achieved by (i) increasing the transcript and protein levels of mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), (ii) shunting tyrosine into the tricarboxylic acid (TCA) cycle to increase fumarate and oxaloacetate which will be converted into PEP by PEPCK-M, and (iii) blocking all the pathways that use PEP downstream gluconeogenesis (i.e., serine synthesis pathway (SSP), glyceroneogenesis and gluconeogenesis). While sequestering host PEP may be critical for this bacterium because it cannot actively carry out glycolysis to produce PEP, excess of this metabolite may be toxic for . The present work provides a more comprehensive view of the major amino acid metabolic pathways involved in the response to pathogen infection in ticks, and provides the basis for further studies to develop novel strategies for the control of granulocytic anaplasmosis.
专性胞内病原体嗜吞噬细胞无形体是人和动物中危及生命疾病的病原体。嗜吞噬细胞无形体是美国、欧洲、非洲和亚洲一种新出现的蜱传病原体，每年感染的人和动物数量不断增加。人们越来越认识到，胞内病原体改变宿主细胞代谢途径以增加在脊椎动物和无脊椎动物宿主中的感染和传播。最近的报告表明，氨基酸在宿主-病原体代谢相互作用中至关重要。在本研究中，在美国嗜吞噬细胞无形体的主要蜱传播媒介肩突硬蜱中进行了全基因组范围内对氨基酸代谢途径成分的搜索，其基因组最近已公布。确定了参与二十种氨基酸合成和降解途径的酶。然后，利用现有的转录组学和蛋白质组学数据来表征蜱组织和ISE6蜱细胞在嗜吞噬细胞无形体感染时氨基酸代谢途径成分的mRNA和蛋白质水平。我们的分析集中在ISE6细胞感染嗜吞噬细胞无形体期间碳水化合物和氨基酸代谢之间的相互作用。结果表明，蜱细胞增加从酪氨酸合成磷酸烯醇式丙酮酸（PEP）以控制嗜吞噬细胞无形体感染。代谢途径分析表明，这是通过以下方式实现的：（i）增加线粒体磷酸烯醇式丙酮酸羧激酶（PEPCK-M）的转录本和蛋白质水平；（ii）将酪氨酸分流到三羧酸（TCA）循环中以增加富马酸和草酰乙酸，它们将由PEPCK-M转化为PEP；（iii）阻断糖异生下游所有使用PEP的途径（即丝氨酸合成途径（SSP）、甘油生成和糖异生）。虽然隔离宿主PEP对这种细菌可能至关重要，因为它不能主动进行糖酵解来产生PEP，但这种代谢物过量可能对嗜吞噬细胞无形体有毒。目前的工作提供了蜱对病原体感染反应中主要氨基酸代谢途径的更全面视图，并为进一步研究开发控制粒细胞无形体病的新策略提供了基础。
