SOCS1 Antagonist–Expressing Recombinant Bacillus Calmette–Guérin Enhances Antituberculosis Protection in a Mouse Model
SOCS1 Antagonist–Expressing Recombinant Bacillus Calmette–Guérin Enhances Antituberculosis Protection in a Mouse Model
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DOI：
10.4049/jimmunol.1800694
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发表时间：
2019-07
期刊：
影响因子：
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通讯作者：
S. Mizuno;S. Soma;Hiroyasu Inada;Tomohiro Kanuma;K. Matsuo;Y. Yasutomi
中科院分区：
文献类型：
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作者：
S. Mizuno;S. Soma;Hiroyasu Inada;Tomohiro Kanuma;K. Matsuo;Y. Yasutomi
关键点rBCG-SOCS 1DN通过激活DC增强Ag特异性T细胞的诱导。Ag特异性T细胞增强增强对M.肺结核感染。细胞因子信号转导抑制因子1（SOCS 1）在JAK/STAT信号转导的负调控中起关键作用，参与天然免疫和随后的适应性免疫。卡介苗（BCG）诱导宿主细胞中SOCS 1表达上调，这可能导致BCG通过抑制JAK/STAT信号通路抑制免疫应答。这可能导致卡介苗的保护作用降低。在目前的研究中，我们评估的免疫反应和保护性的重组卡介苗分泌的显性负突变体的SOCS 1分子（rBCG-SOCS 1DN）的效力。用rBCG-SOCS 1DN或携带空质粒载体的亲本BCG东京疫苗株（rBCG-pSO）免疫C57 BL/6小鼠。与rBCG-pSO相比，rBCG-SOCS 1DN增强了骨髓来源的树突状细胞的活化和T细胞的活化。rBCG-SOCS 1DN免疫小鼠脾细胞产生IFN-γ、TNF-α和IL-6的量高于rBCG-pSO免疫小鼠。此外，当免疫小鼠感染高致病性M.吸入性肺结核菌株。这些结果为rBCG-SOCS 1DN作为一种有效的M.结核病疫苗与rBCG作为宿主细胞免疫调节工具的新概念。
Key Points rBCG-SOCS1DN enhanced the induction of Ag-specific T cells via the activation of DC. Ag-specific T cell enhancement enhanced protection against M. tuberculosis infection. Suppressor of cytokine signaling 1 (SOCS1) plays a key role in the negative regulation of JAK/STAT signaling, which is involved in innate immunity and subsequent adaptive immunity. Bacillus Calmette–Guérin (BCG) induces upregulation of SOCS1 expression in host cells, which may lead to the suppression of immune responses by BCG via inhibition of the JAK/STAT signaling pathway. This might cause A reduction in the protective effect of a BCG vaccine. In the current study, we assessed the immune responses to and the protective efficacy of a recombinant BCG secreting a dominant negative mutant of the SOCS1 molecule (rBCG-SOCS1DN). C57BL/6 mice were immunized with rBCG-SOCS1DN or parental BCG Tokyo vaccine strain harboring an empty plasmid vector (rBCG-pSO). rBCG-SOCS1DN enhanced the activation of bone marrow–derived dendritic cells and the activation of T cells compared with those with rBCG-pSO. The amounts of IFN-γ, TNF-α, and IL-6 produced by splenocytes of rBCG-SOCS1DN–immunized mice were larger than those produced by splenocytes of rBCG-pSO–immunized mice. Moreover, the rBCG-SOCS1DN–immunized mice showed a substantial reduction in the number of CFU of Mycobacterium tuberculosis in the lungs and spleens compared with that in control BCG-immunized mice when the immunized mice were infected with a highly pathogenic M. tuberculosis strain by inhalation. These findings provide evidence for the possibility of rBCG-SOCS1DN being an effective M. tuberculosis vaccine with a novel concept of rBCG as a tool for immunomodulation in host cells.