Zinc piracy as a mechanism of Neisseria meningitidis for evasion of nutritional immunity.
Zinc piracy as a mechanism of Neisseria meningitidis for evasion of nutritional immunity.
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DOI：
10.1371/journal.ppat.1003733
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发表时间：
2013-10
期刊：
影响因子：
6.7
通讯作者：
Tommassen J
中科院分区：
文献类型：
--
作者：
Stork M;Grijpstra J;Bos MP;Mañas Torres C;Devos N;Poolman JT;Chazin WJ;Tommassen J
革兰氏阴性细菌的外膜充当渗透性屏障，保护这些细菌免受环境中有害化合物的侵害。大多数营养物质通过称为孔蛋白的成孔蛋白被动扩散穿过外膜。然而，只有细胞外营养物质浓度较高时，扩散才能满足生长要求。在脊椎动物宿主中，必需营养金属的隔离是限制入侵病原体生长的重要防御机制，这一过程称为“营养免疫”。从环境中获取稀缺营养物质是由外膜中的受体在需要能量的过程中介导的。最有特征的受体涉及铁的获取。在这项研究中，我们鉴定了脑膜炎奈瑟菌（脓毒症和脑膜炎的病原体）中迄今为止未知的受体。当细菌在锌限制下生长时，会诱导这种受体（称为 CbpA）的表达。我们证明，CbpA 充当钙卫蛋白的受体，钙卫蛋白是一种由中性粒细胞和其他细胞大量产生的蛋白质，已被证明可以通过螯合 Zn2+ 和 Mn2+ 离子来限制细菌生长。 CbpA 的表达使得脑膜炎奈瑟菌能够在钙卫蛋白存在的情况下生存和繁殖，并使用钙卫蛋白作为锌源。除了 CbpA 之外，该过程还需要 TonB 蛋白，它将跨内膜的质子梯度能量与受体介导的跨外膜运输耦合。发现 CbpA 在所有检测的脑膜炎奈瑟氏球菌菌株中表达，这与细菌驻留在宿主体内时该蛋白质的重要作用一致。总之，我们的结果表明，脑膜炎奈瑟菌能够破坏人类宿主的重要防御机制，并利用钙卫蛋白促进其生长。必需营养金属的封存是脊椎动物用来限制入侵病原体生长的第一道防线，这一过程称为“营养免疫”。作为这种防御机制的一部分，中性粒细胞和其他细胞会产生大量的钙卫蛋白，这种蛋白质通过螯合 Zn2+ 和 Mn2+ 离子来限制细菌生长。我们在此证明，人类鼻咽部的脑膜炎奈瑟菌偶尔会引起败血症和脑膜炎，它能够在钙卫蛋白存在的情况下生存和繁殖。脑膜炎奈瑟菌通过过量产生称为 CbpA 的外膜蛋白来应对锌的限制，CbpA 充当钙卫蛋白的受体，并使细菌能够利用钙卫蛋白作为锌源。脑膜炎奈瑟氏球菌利用钙卫蛋白作为锌源的能力颠覆了宿主的重要防御机制，并为宿主与病原体的军备竞赛增添了新的机制。
The outer membrane of Gram-negative bacteria functions as a permeability barrier that protects these bacteria against harmful compounds in the environment. Most nutrients pass the outer membrane by passive diffusion via pore-forming proteins known as porins. However, diffusion can only satisfy the growth requirements if the extracellular concentration of the nutrients is high. In the vertebrate host, the sequestration of essential nutrient metals is an important defense mechanism that limits the growth of invading pathogens, a process known as “nutritional immunity.” The acquisition of scarce nutrients from the environment is mediated by receptors in the outer membrane in an energy-requiring process. Most characterized receptors are involved in the acquisition of iron. In this study, we characterized a hitherto unknown receptor from Neisseria meningitidis, a causative agent of sepsis and meningitis. Expression of this receptor, designated CbpA, is induced when the bacteria are grown under zinc limitation. We demonstrate that CbpA functions as a receptor for calprotectin, a protein that is massively produced by neutrophils and other cells and that has been shown to limit bacterial growth by chelating Zn2+ and Mn2+ ions. Expression of CbpA enables N. meningitidis to survive and propagate in the presence of calprotectin and to use calprotectin as a zinc source. Besides CbpA, also the TonB protein, which couples energy of the proton gradient across the inner membrane to receptor-mediated transport across the outer membrane, is required for the process. CbpA was found to be expressed in all N. meningitidis strains examined, consistent with a vital role for the protein when the bacteria reside in the host. Together, our results demonstrate that N. meningitidis is able to subvert an important defense mechanism of the human host and to utilize calprotectin to promote its growth. The sequestration of essential nutrient metals is a first line of defense used by vertebrates to limit the growth of invading pathogens, a process termed “nutritional immunity.” As a part of this defense mechanism, neutrophils and other cells produce massive amounts of calprotectin, a protein that limits bacterial growth by chelating Zn2+ and Mn2+ ions. We demonstrate here that Neisseria meningitidis, a resident of the human nasopharynx that occasionally causes sepsis and meningitis, is able to survive and propagate in the presence of calprotectin. N. meningitidis responds to zinc limitation by the overproduction of an outer membrane protein, called CbpA, that functions as a receptor for calprotectin and enables the bacteria to utilize calprotectin as zinc source. The ability of N. meningitidis to use calprotectin as a zinc source subverts an important defense mechanism of the host and adds a new mechanism to the host-pathogens arms race.
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影响因子：
3.1
作者：
Bos, MP;Tommassen, J
通讯作者：
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影响因子：
7.8
作者：
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3.2
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