Comparison of immunogenicity and vaccine efficacy between heat-shock proteins, HSP70 and GrpE, in the DnaK operon of Mycobacterium tuberculosis.
Comparison of immunogenicity and vaccine efficacy between heat-shock proteins, HSP70 and GrpE, in the DnaK operon of Mycobacterium tuberculosis.
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DOI：
10.1038/s41598-018-32799-z
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发表时间：
2018-09-26
影响因子：
4.6
通讯作者：
Shin SJ
中科院分区：
文献类型：
--
作者：
Kim WS;Kim JS;Kim HM;Kwon KW;Eum SY;Shin SJ
结核分枝杆菌（Mtb）中组成型表达、生长过程中过表达、生存必需和高度保守的抗原（Ags）如果诱导适当的抗Mtb Th 1免疫应答，则可能是良好的疫苗靶点。在这种情况下，Mtb的应激反应相关抗原可能作为疫苗开发的有吸引力的靶标，因为它们在体内Mtb感染期间快速表达并上调。我们的小组最近证明，GrpE，编码的rv 0351作为辅助因子的热休克蛋白70（HSP 70）的DnaK操纵子，是一种新的免疫激活剂，与DC相互作用，产生Th 1偏向的记忆T细胞在抗原特异性的方式。在这项研究中，GrpE作为一种亚单位疫苗进行了评估，与众所周知的HSP 70相比，针对高毒力Mtb北京K株。在Mtb感染小鼠的肺和脾中，HSP 70和GrpE特异性效应/记忆T细胞均扩增至与ESAT-6刺激相似的程度，但GrpE仅在Mtb K感染的晚期和早期产生与ESAT-6刺激相似水平的IFN-γ，表明GrpE作为T细胞抗原被宿主免疫系统高度识别。用GrpE亚单位疫苗免疫的小鼠显示出增强的抗原特异性IFN-γ和血清IgG 2c应答，沿着肺中的抗原特异性效应/记忆T细胞扩增。此外，GrpE免疫显著诱导Mtb K感染小鼠肺中多功能Th 1型CD 4 + T细胞共表达IFN-γ、TNF-α和IL-2，而HSP 70免疫诱导混合Th 1/Th 2免疫应答。GrpE-免疫在细菌减少和改善炎症方面比HSP 70-免疫赋予更显著的保护作用，伴随着GrpE特异性多功能CD 4 + T细胞的显著持久性。这些结果表明，GrpE是一个很好的疫苗抗原成分的多抗原Mtb亚单位疫苗的发展，通过产生Th 1偏置的记忆T细胞与多功能的能力，并赋予持久的保护，对高毒力的Mtb K。
Antigens (Ags) in Mycobacterium tuberculosis (Mtb) that are constitutively expressed, overexpressed during growth, essential for survival, and highly conserved may be good vaccine targets if they induce the appropriate anti-Mtb Th1 immune response. In this context, stress response-related antigens of Mtb might serve as attractive targets for vaccine development as they are rapidly expressed and are up-regulated during Mtb infection in vivo. Our group recently demonstrated that GrpE, encoded by rv0351 as a cofactor of heat-shock protein 70 (HSP70) in the DnaK operon, is a novel immune activator that interacts with DCs to generate Th1-biased memory T cells in an antigen-specific manner. In this study, GrpE was evaluated as a subunit vaccine in comparison with the well-known HSP70 against the hyper-virulent Mtb Beijing K-strain. Both HSP70- and GrpE-specific effector/memory T cells expanded to a similar extent as those stimulated with ESAT-6 in the lung and spleen of Mtb-infected mice, but GrpE only produced a similar level of IFN-γ to that produced by ESAT-6 stimulation during the late phase and the early phase of Mtb K infection, indicating that GrpE is highly-well recognised by the host immune system as a T cell antigen. Mice immunised with the GrpE subunit vaccine displayed enhanced antigen-specific IFN-γ and serum IgG2c responses along with antigen-specific effector/memory T cell expansion in the lungs. In addition, GrpE-immunisation markedly induced multifunctional Th1-type CD4+ T cells co-expressing IFN-γ, TNF-α, and IL-2 in the lungs of Mtb K-infected mice, whereas HSP70-immunisation induced mixed Th1/Th2 immune responses. GrpE-immunisation conferred a more significant protective effect than that of HSP70-immunisation in terms of bacterial reduction and improved inflammation, accompanied by the remarkable persistence of GrpE-specific multifunctional CD4+ T cells. These results suggest that GrpE is an excellent vaccine antigen component for the development of a multi-antigenic Mtb subunit vaccine by generating Th1-biased memory T cells with multifunctional capacity, and confers durable protection against the highly virulent Mtb K.
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影响因子：
7.3
作者：
Dockrell HM;Smith SG
通讯作者：
Smith SG
影响因子：
--
作者：
Kim WS;Kim JS;Cha SB;Kim H;Kwon KW;Kim SJ;Han SJ;Choi SY;Cho SN;Park JH;Shin SJ
通讯作者：
Shin SJ
影响因子：
4.6
作者：
Lyadova IV;Panteleev AV
通讯作者：
Panteleev AV
影响因子：
4.4
作者：
Lindenstrom, Thomas;Knudsen, Niels Peter Hell;Andersen, Peter
通讯作者：
Andersen, Peter
影响因子：
4.8
作者：
Bulut, Y;Michelsen, KS;Arditi, M
通讯作者：
Arditi, M