Rv2346c enhances mycobacterial survival within macrophages by inhibiting TNF-α and IL-6 production via the p38/miRNA/NF-κB pathway.
Rv2346c enhances mycobacterial survival within macrophages by inhibiting TNF-α and IL-6 production via the p38/miRNA/NF-κB pathway.
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Rv2346c 通过 p38/miRNA/NF-kappaB 途径抑制 TNF-α 和 IL-6 的产生，从而增强巨噬细胞内分枝杆菌的存活率
DOI：
10.1038/s41426-018-0162-6
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发表时间：
2018-09-19
影响因子：
13.2
通讯作者：
Feng G
中科院分区：
文献类型：
--
作者：
Yao J;Du X;Chen S;Shao Y;Deng K;Jiang M;Liu J;Shen Z;Chen X;Feng G
结核分枝杆菌（Mycobacterium tuberculosis，Mtb）的胞内存活在结核病的发病机制中起着重要作用。Mtb Rv 2346 c是6-kDa早期分泌抗原靶蛋白家族的成员，已知其抑制宿主免疫应答以促进巨噬细胞中的杆菌持久性。然而，Rv 2346 c参与Mtb发病机制的机制尚不清楚。在本研究中，重组Rv 2346 c蛋白的合成和用于治疗卡介苗（BCG）感染的巨噬细胞。结果表明，Rv 2346 c能抑制BCG感染的巨噬细胞的增殖，提高BCG在巨噬细胞中的存活率。在BCG感染过程中，肿瘤坏死因子-α（TNF-α）和白细胞介素（IL-6）表达上调，而Rv 2346 c则下调。其他实验表明，BCG感染的巨噬细胞中的核转录因子-κB（NF-κB）诱导TNF-α和IL-6的产生。此外，miR-155和miR-99 b对NF-κB有抑制作用，p38促进了这些miRNAs的表达。此外，Rv 2346 c显示降低NF-κB的活化，而其增强p38的磷酸化以及miR-155和miR-99 B的表达。Rv 2346 c的功能也在Mtb感染的小鼠中得到验证。结果表明，Rv 2346 c在体内增加了观察到的细菌负荷和肺损伤，并下调了TNF-α和IL-6。总之，我们的研究结果表明，Rv 2346 c通过p38/miRNA/NF-κB途径依赖性方式抑制TNF-α和IL-6的产生来增强分枝杆菌在巨噬细胞中的存活，这表明Rv 2346 c在Mt B感染中作为关键毒力因子起作用，并且具有作为抗结核治疗靶点的潜在用途。
The intracellular survival of Mycobacterium tuberculosis (Mtb) has a central role in the pathogenesis of tuberculosis. Mtb Rv2346c is a member of 6-kDa early secreted antigenic target family of proteins, which are known to inhibit the host immune responses to promote bacillary persistence in macrophages. However, the mechanism through which Rv2346c participates in Mtb pathogenesis is unclear. In the present study, recombinant Rv2346c protein was synthesized and used to treat Bacillus Calmette–Guérin (BCG)-infected macrophages. The results showed that Rv2346c inhibited the proliferation of BCG-infected macrophages and enhanced the survival of BCG in macrophages. Tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were upregulated during BCG infection but downregulated by Rv2346c. Additional experiments showed that nuclear transcription factor-κB (NF-κB) in BCG-infected macrophages induced the production of TNF-α and IL-6. In addition, miR-155 and miR-99b had a suppressive effect on NF-κB, and the expression of these miRNAs was promoted by p38. Furthermore, Rv2346c was shown to decrease the activation of NF-κB, whereas it enhanced the phosphorylation of p38 and the expression of miR-155 and miR-99b. The function of Rv2346c was also verified in Mtb-infected mice. The results showed that Rv2346c increased the observed bacterial load and lung injury and downregulated TNF-α and IL-6 in vivo. Overall, our results reveal that Rv2346c enhances mycobacterial survival in macrophages via inhibiting the production of TNF-α and IL-6 in a p38/miRNA/NF-κB pathway-dependent manner, suggesting that Rv2346c acts as a crucial virulence factor in Mtb infection and has potential use as a target for anti-tuberculosis therapy.
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影响因子：
11.1
作者：
Hu S;He W;Du X;Yang J;Wen Q;Zhong XP;Ma L
通讯作者：
Ma L
重组卡介苗疫苗 VPM1002：准备进行临床功效测试。
影响因子：
7.3
作者：
Nieuwenhuizen NE;Kulkarni PS;Shaligram U;Cotton MF;Rentsch CA;Eisele B;Grode L;Kaufmann SHE
通讯作者：
Kaufmann SHE
结核分枝杆菌感染中的模式识别受体和细胞因子 - 双刃剑？
影响因子：
--
作者：
Hossain MM;Norazmi MN
通讯作者：
Norazmi MN
DOI：
10.1016/j.tube.2013.08.004
发表时间：
2013-11
期刊：
Tuberculosis (Edinburgh, Scotland)
影响因子：
--
作者：
Harapan H;Fitra F;Ichsan I;Mulyadi M;Miotto P;Hasan NA;Calado M;Cirillo DM
通讯作者：
Cirillo DM
影响因子：
3.1
作者：
Ladel, CH;Blum, C;Kaufmann, SHE
通讯作者：
Kaufmann, SHE