The Meningococcal Cysteine Transport System Plays a Crucial Role in Neisseria meningitidis Survival in Human Brain Microvascular Endothelial Cells.
The Meningococcal Cysteine Transport System Plays a Crucial Role in Neisseria meningitidis Survival in Human Brain Microvascular Endothelial Cells.
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脑膜炎球菌半胱氨酸转运系统在人脑微血管内皮细胞中脑膜炎奈瑟氏菌的存活中发挥着至关重要的作用。
DOI：
10.1128/mbio.02332-18
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发表时间：
2018
期刊：
影响因子：
6.4
通讯作者：
Yanagisawa,Tatsuo
中科院分区：
文献类型：
--
作者：
Takahashi,Hideyuki;Watanabe,Haruo;Kim,KwangSik;Yokoyama,Shigeyuki;Yanagisawa,Tatsuo
虽然脑膜炎奈瑟氏菌通常以无症状的鼻咽携带状态存在，但它可能通过侵入体内更深的部位而在人类中引起潜在的致命疾病，如败血症或脑膜炎。由于人体细胞的营养成分并不总是有利于脑膜炎球菌，N。脑膜炎需要从宿主环境中吸取营养。在本研究中，半胱氨酸的脑膜炎球菌半胱氨酸转运系统（CTS）的利用脑膜炎球菌感染的发病机制进行了分析。A N。脑膜炎病毒株在编码半胱氨酸结合蛋白（cbp）的三个基因中的一个基因缺陷，表现出比野生型菌株低约100倍的人脑微血管内皮细胞（HBMEC）的内化。这一缺陷通过三个基因的互补作用得以恢复，HBMEC内化的感染性表型与半胱氨酸摄取活性相关。然而，有效积累ezrin下观察bp突变体。bp突变体在HBMEC中的细胞内存活率显著降低，而谷胱甘肽浓度和对活性氧的抵抗力却没有相应的降低，bp突变体在完全培养基中生长良好，但在添加低于300 μM半胱氨酸的合成培养基中生长不好。以半胱氨酸浓度在人体细胞和其他体液，包括血液和脑脊液，考虑到，目前的结果共同表明，脑膜炎球菌CTS是至关重要的收购半胱氨酸从人体细胞和参与脑膜炎球菌营养vitrificity.IMPORTANCENeisseria脑膜炎奈瑟氏菌定植在鼻咽部的人作为一个独特的主机，并有许多菌株是氨基酸营养缺陷型为他们的生长。脑膜炎球菌可引起侵袭性脑膜炎球菌病（IMD），如败血症和脑膜炎。脑膜炎通过上皮和内皮屏障并浸润到血液和脑脊液以及上皮和内皮细胞中。然而，脑膜炎球菌的营养物质，包括半胱氨酸，即使在炎症期间，当它更深地浸润人体时，也变得不那么丰富，例如N。脑膜炎必须获得营养以便在人类中存活/持续、传播和增殖。这是第一项探讨脑膜炎球菌半胱氨酸获得与脑膜炎球菌感染发病机制之间关系的研究。本研究的结果提供了深入了解营养缺陷型病原体在宿主中获得营养的机制，也可能有助于IMD治疗和预防策略的发展。
While Neisseria meningitidis typically exists in an asymptomatic nasopharyngeal carriage state, it may cause potentially lethal diseases in humans, such as septicemia or meningitis, by invading deeper sites in the body. Since the nutrient compositions of human cells are not always conducive to meningococci, N. meningitidis needs to exploit nutrients from host environments. In the present study, the utilization of cysteine by the meningococcal cysteine transport system (CTS) was analyzed for the pathogenesis of meningococcal infections. A N. meningitidis strain deficient in one of the threectsgenes annotated as encoding cysteine-binding protein (cbp) exhibited approximately 100-fold less internalization into human brain microvascular endothelial cells (HBMEC) than the wild-type strain. This deficiency was restored by complementation with the threectsgenes together, and the infectious phenotype of HBMEC internalization correlated with cysteine uptake activity. However, efficient accumulation of ezrin was observed beneath thecbpmutant. The intracellular survival of thecbpmutant in HBMEC was markedly reduced, whereas equivalent reductions of glutathione concentrations and of resistance to reactive oxygens species in thecbpmutant were not found. Thecbpmutant grew well in complete medium but not in synthetic medium supplemented with less than 300 μM cysteine. Taking cysteine concentrations in human cells and other body fluids, including blood and cerebrospinal fluid, into consideration, the present results collectively suggest that the meningococcal CTS is crucial for the acquisition of cysteine from human cells and participates in meningococcal nutrient virulence.IMPORTANCENeisseria meningitidis colonizes at a nasopharynx of human as a unique host and has many strains that are auxotrophs for amino acids for their growth. To cause invasive meningococcal diseases (IMD) such as sepsis and meningitis, N. meningitidis passes through epithelial and endothelial barriers and infiltrates into blood and cerebrospinal fluid as well as epithelial and endothelial cells. However, meningococcal nutrients, including cysteine, become less abundant when it more deeply infiltrates the human body even during inflammation, such that N. meningitidis has to acquire nutrients in order to survive/persist, disseminate, and proliferate in humans. This was the first study to examine the relationship between meningococcal cysteine acquisition and the pathogenesis of meningococcal infections. The results of the present study provide insights into the mechanisms by which pathogens with auxotrophs acquire nutrients in hosts and may also contribute to the development of treatments and prevention strategies for IMD.