O-mannosylation of the Mycobacterium tuberculosis adhesin Apa is crucial for T cell antigenicity during infection but is expendable for protection.
O-mannosylation of the Mycobacterium tuberculosis adhesin Apa is crucial for T cell antigenicity during infection but is expendable for protection.
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DOI：
10.1371/journal.ppat.1003705
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Sable SB
中科院分区：
文献类型：
--
作者：
Nandakumar S;Kannanganat S;Dobos KM;Lucas M;Spencer JS;Fang S;McDonald MA;Pohl J;Birkness K;Chamcha V;Ramirez MV;Plikaytis BB;Posey JE;Amara RR;Sable SB
糖基化是自然界中最丰富的翻译后多肽链修饰。尽管来自许多微生物病原体的蛋白质抗原的碳水化合物修饰构成了 B 细胞表位的重要组成部分，但在 T 细胞免疫中的作用尚不完全清楚。在这里，我们使用 ELISPOT 和多色流式细胞术，证明结核分枝杆菌 (Mtb) 粘附素 Apa 的 O-甘露糖基化对其感染后人和小鼠的 T 细胞抗原性至关重要。然而，用甘露糖基化和非甘露糖基化 Apa 进行亚单位疫苗接种可诱导相当程度和质量的 T 细胞反应，并在小鼠中提供类似水平的针对 Mtb 攻击的保护作用。两种形式同样改善了亚单位加强后老年小鼠中卡介苗疫苗诱导的减弱保护作用。因此，Apa 的 O-甘露糖基化对于抗原性是必需的，但对于其在小鼠中的免疫原性和保护功效来说似乎是可有可无的。这些结果对于使用翻译后修饰的蛋白质（例如糖蛋白）开发针对结核病等传染病的亚单位疫苗具有重要意义。 结核分枝杆菌 (Mtb) 是有史以来最具破坏性的细菌病原体，每年导致约 140 万人死亡。结核分枝杆菌用糖残基修饰其多种蛋白质，从而影响许多生物事件。然而，这种糖修饰以及由此产生的碳水化合物和糖肽表位在感染期间或疫苗接种后塑造 T 细胞反应中的重要性尚不清楚。在这里，我们发现 Mtb Apa 蛋白的碳水化合物修饰显着影响人类和小鼠感染后特异性 T 细胞反应的程度，但对 T 细胞反应的多功能性和质量影响很小。然而，当用作亚单位疫苗或二甲基双十八烷基溴化铵 (DDA)-单磷酰脂质 A (MPL) 佐剂中的 BCG 加强疫苗来对抗小鼠的强毒 Mtb 感染时，Apa 的糖基化会影响 T 细胞免疫原性和保护功效。我们的结果表明，微生物蛋白抗原的碳水化合物修饰可能并不总是对于保护至关重要，因为我们未修饰的重组蛋白足以用于亚单位疫苗接种。总之，我们的数据强调需要了解增强的 Apa 糖蛋白特异性 T 细胞反应在感染过程中的作用。
Glycosylation is the most abundant post-translational polypeptide chain modification in nature. Although carbohydrate modification of protein antigens from many microbial pathogens constitutes important components of B cell epitopes, the role in T cell immunity is not completely understood. Here, using ELISPOT and polychromatic flow cytometry, we show that O-mannosylation of the adhesin, Apa, of Mycobacterium tuberculosis (Mtb) is crucial for its T cell antigenicity in humans and mice after infection. However, subunit vaccination with both mannosylated and non-mannosylated Apa induced a comparable magnitude and quality of T cell response and imparted similar levels of protection against Mtb challenge in mice. Both forms equally improved waning BCG vaccine-induced protection in elderly mice after subunit boosting. Thus, O-mannosylation of Apa is required for antigenicity but appears to be dispensable for its immunogenicity and protective efficacy in mice. These results have implications for the development of subunit vaccines using post-translationally modified proteins such as glycoproteins against infectious diseases like tuberculosis. Mycobacterium tuberculosis (Mtb) is the most devastating bacterial pathogen of all time that kills approximately 1.4 million people each year. Mtb modifies several of its proteins with sugar residues that influence many biological events. However, the significance of such sugar decorations and resulting carbohydrate and glycopeptide epitopes in shaping the T cell response during infection or after vaccination is insufficiently understood. Here, we show that the carbohydrate modifications of the Mtb Apa protein strikingly influence the magnitude of specific T cell responses in humans and mice after infection, but have only minor effect on the polyfunctionality and quality of T cell responses. The glycosylation of Apa was, however, expendable for T cell immunogenicity and protective efficacy when used either as a subunit vaccine or as a BCG-booster vaccine in dimethyl-dioctadecyl ammonium bromide (DDA)-monophosphoryl lipid A (MPL) adjuvant against virulent Mtb infection in mice. Our results suggest that the carbohydrate modification of microbial protein antigens may not always be critical for protection as our unmodified recombinant protein was sufficient for subunit vaccination. Together, our data underline the need to understand the role of heightened Apa glycoprotein-specific T cell responses in infection processes.
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影响因子：
16.8
作者：
通讯作者：
--
DOI：
10.1038/nri2569
发表时间：
2009-07
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Geijtenbeek TB;Gringhuis SI
通讯作者：
Gringhuis SI
影响因子：
3.2
作者：
Dobos, KM;Khoo, KH;Belisle, JT
通讯作者：
Belisle, JT
影响因子：
3.1
作者：
Ferraz, JC;Stavropoulos, E;Tascon, RE
通讯作者：
Tascon, RE
影响因子：
56.9
作者：
Brightbill, HD;Libraty, DH;Modlin, RL
通讯作者：
Modlin, RL