The Recombinant BCG ΔureC::hly Vaccine Targets the AIM2 Inflammasome to Induce Autophagy and Inflammation
The Recombinant BCG ΔureC::hly Vaccine Targets the AIM2 Inflammasome to Induce Autophagy and Inflammation
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DOI：
10.1093/infdis/jiu675
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发表时间：
2015-06-01
影响因子：
6.4
通讯作者：
Kaufmann, Stefan H. E.
中科院分区：
文献类型：
--
作者：
Saiga, Hiroyuki;Nieuwenhuizen, Natalie;Kaufmann, Stefan H. E.
背景。重组BCG。在临床前研究中，ureC::hly （rBCG）候选疫苗比亲本卡介苗（pBCG）具有更好的结核病保护作用，并已成功完成2a期临床试验。然而，rBCG疫苗的优越疗效的机制仍不完全清楚。方法分别用pBCG和rBCG感染欧洲整体THP-1巨噬细胞，观察炎症小体的活化和自噬情况。此外，接种pBCG或rBCG的小鼠，接种后第1天通过芯片分析引流淋巴结的基因表达。结果：在感染rBCG的巨噬细胞细胞质中检测到欧洲整合的bcg来源的DNA。rBCG感染与黑色素瘤2 （AIM2）炎症小体激活增强、半胱天冬酶激活增加、白细胞介素(IL)-1 β和IL-18的产生以及AIM2依赖性和干扰素刺激因子基因（STING）依赖性自噬的诱导相关。同样，接种rBCG的小鼠也表现出Il-1 β、Il-18和Tmem173（跨膜蛋白173，也称为STING）的早期表达增加。整体rBCG刺激AIM2炎性体激活和自噬，表明这些细胞自主功能应用于改进疫苗设计。
Background. The recombinant BCG.ureC::hly (rBCG) vaccine candidate induces improved protection against tuberculosis over parental BCG (pBCG) in preclinical studies and has successfully completed a phase 2a clinical trial. However, the mechanisms responsible for the superior vaccine efficacy of rBCG are still incompletely understood. Here, we investigated the underlying biological mechanisms elicited by the rBCG vaccine candidate relevant to its protective efficacy.Methods.aEuro integral THP-1 macrophages were infected with pBCG or rBCG, and inflammasome activation and autophagy were evaluated. In addition, mice were vaccinated with pBCG or rBCG, and gene expression in the draining lymph nodes was analyzed by microarray at day 1 after vaccination.Results.aEuro integral BCG-derived DNA was detected in the cytosol of rBCG-infected macrophages. rBCG infection was associated with enhanced absent in melanoma 2 (AIM2) inflammasome activation, increased activation of caspases and production of interleukin (IL)-1 beta and IL-18, as well as induction of AIM2-dependent and stimulator of interferon genes (STING)-dependent autophagy. Similarly, mice vaccinated with rBCG showed early increased expression of Il-1 beta, Il-18, and Tmem173 (transmembrane protein 173; also known as STING).Conclusions.aEuro integral rBCG stimulates AIM2 inflammasome activation and autophagy, suggesting that these cell-autonomous functions should be exploited for improved vaccine design.