Recombinant BCG::Rv2645 elicits enhanced protective immunity compared to BCG in vivo with induced ISGylation-related genes and Th1 and Th17 responses
Recombinant BCG::Rv2645 elicits enhanced protective immunity compared to BCG in vivo with induced ISGylation-related genes and Th1 and Th17 responses
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与 BCG 相比，重组 BCG::Rv2645 在体内可引发增强的保护性免疫，诱导 ISGylation 相关基因以及 Th1 和 Th17 反应
DOI：
10.1016/j.vaccine.2018.04.025
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发表时间：
2018
期刊：
影响因子：
5.5
通讯作者：
Zhang Xiao Lian
中科院分区：
文献类型：
--
作者：
Luo Wei;Qu Zilu;Zhang Lingyun;Xie Yan;Luo Fengling;Tan Yang;Pan Qin;Zhang Xiao Lian
有必要开发针对结核病的保护性疫苗。最近，我们从m的缺失13区（RD13）中鉴定出一种免疫优势t细胞抗原Rv2645。肺结核(M。tb) H37Rv，该病毒在卡介苗（BCG）中缺失。本文构建了表达Rv2645的重组BCG，即BCG::Rv2645。与BCG相比，我们发现BCG::Rv2645提高了树突状细胞（dc）的抗原呈递能力，引发了更强的Th1和Th17反应，更高的cd44 - high - cd62低效应记忆CD4+T细胞（TEM），更少的T调节细胞（Treg）和调节性B10。重要的是，BCG::Rv2645对恶性m的保护作用增强。小鼠和恒河猴均感染了tbH37Rv，表现出较轻的病理和减少的病原体。此外，转录组学分析和逆转录定量实时PCR显示，Rv2645刺激后，脾细胞和巨噬细胞中isg酰化（Isg）相关基因如干扰素刺激基因15 (Isg15)， Th1和th17相关基因如干扰素-γ (IFN-γ)和白细胞介素- 17a （IL-17A）的mRNA水平显著上调。本研究表明，BCG::Rv2645是一种具有较强保护性免疫的结核疫苗候选株。Rv2645诱导的Th1/Th17免疫应答增强和isgyylation相关基因上调可能是促成BCG::Rv2645保护性免疫的主要因素。
There is a need to develop protective vaccines against tuberculosis (TB). Recently, we identified an immunodominant T-cell antigen, Rv2645, from the region of deletion 13 (RD13) ofM. tuberculosis(M. tb) H37Rv, which is absent in Bacille Calmette-Guérin (BCG). Here, a recombinant BCG expressing Rv2645, namely, BCG::Rv2645, was constructed. Compared to BCG, we found that BCG::Rv2645 improved the antigen presentation capacity of dendritic cells (DCs) and elicited much stronger Th1 and Th17 responses, higher CD44highCD62loweffector memory CD4+T cells (TEM), and fewer T regulated cells (Treg) and regulatory B10 in mice. Importantly, BCG::Rv2645 exhibited enhanced protective efficacy against virulentM. tbH37Rv challenge in both mice and rhesus monkeys, showing less severe pathology and reduced pathogens. Further, transcriptomic analysis and reverse transcription-quantitative real time PCR revealed that the mRNA levels of ISGylation (Isg)-related genes such as interferon-stimulated gene 15 (Isg15), and Th1- and Th17-related genes such as interferon-γ (IFN-γ) and interleukin-17A (IL-17A) were significantly up-regulated in splenocytes and macrophages after stimulation with Rv2645. This study shows that BCG::Rv2645 is a promising TB vaccine candidate with enhanced protective immunity. The enhanced Th1/Th17 immune responses and up-regulation of ISGylation-related genes induced by Rv2645 may be major factors contributing to the protective immunity of BCG::Rv2645.