Host sirtuin 2 as an immunotherapeutic target against tuberculosis
Host sirtuin 2 as an immunotherapeutic target against tuberculosis
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DOI：
10.7554/elife.55415
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发表时间：
2020-07-22
期刊：
影响因子：
7.7
通讯作者：
Nandicoori, Vinay Kumar
中科院分区：
文献类型：
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作者：
Bhaskar, Ashima;Kumar, Santosh;Nandicoori, Vinay Kumar
结核分枝杆菌(Mtb)利用过多的机制劫持宿主的防御机制，使其能够成功地生存、增殖和持久。在这里，我们发现Mtb上调了关键的表观遗传调节因子之一，NAD+依赖的组蛋白脱乙酰酶Sirtuin 2(SIRT2)，SIRT2在感染时转移到细胞核并去乙酰化组蛋白H3K18，从而调节宿主转录组，从而增强巨噬细胞的激活。此外，在结核分枝杆菌特异性T细胞中，SIRT2在K310处去乙酰化NFKB-P65以调节T辅助细胞的分化。SIRT2的药理抑制限制了结核分枝杆菌药物敏感株和耐药株的细胞内生长，并增强了一线抗结核药物异烟肼在小鼠感染模型中的疗效。SIRT2抑制剂治疗的小鼠表现出减少了细菌负荷，减少了疾病病理，并增加了Mtb特异性保护性免疫反应。总体而言，这项研究提供了结核分枝杆菌感染、表观遗传学和宿主免疫反应之间的联系，可以利用这些联系来实现治疗效益。
Mycobacterium tuberculosis (Mtb) employs plethora of mechanisms to hijack the host defence machinery for its successful survival, proliferation and persistence. Here, we show that Mtb upregulates one of the key epigenetic modulators, NAD+ dependent histone deacetylase Sirtuin 2 (SIRT2), which upon infection translocate to the nucleus and deacetylates histone H3K18, thus modulating the host transcriptome leading to enhanced macrophage activation. Furthermore, in Mtb specific T cells, SIRT2 deacetylates NFKB-p65 at K310 to modulate T helper cell differentiation. Pharmacological inhibition of SIRT2 restricts the intracellular growth of both drug-sensitive and resistant strains of Mtb and enhances the efficacy of front line anti-TB drug Isoniazid in the murine model of infection. SIRT2 inhibitor-treated mice display reduced bacillary load, decreased disease pathology and increased Mtb-specific protective immune responses. Overall, this study provides a link between Mtb infection, epigenetics and host immune response, which can be exploited to achieve therapeutic benefits.