New live attenuated tuberculosis vaccine MTBVAC induces trained immunity and confers protection against experimental lethal pneumonia

Among infectious diseases, tuberculosis is the leading cause of death worldwide, and represents a serious threat, especially in developing countries. The protective effects of Bacillus Calmette-Guerin (BCG), the current vaccine against tuberculosis, have been related not only to specific induction of T-cell immunity, but also with the long-term epigenetic and metabolic reprogramming of the cells from the innate immune system through a process termed trained immunity. Here we show that MTBVAC, a live attenuated strain of Mycobacterium tuberculosis, safe and immunogenic against tuberculosis antigens in adults and newborns, is also able to generate trained immunity through the induction of glycolysis and glutaminolysis and the accumulation of histone methylation marks at the promoters of proinflammatory genes, facilitating an enhanced response after secondary challenge with non-related bacterial stimuli. Importantly, these findings in human primary myeloid cells are complemented by a strong MTBVAC-induced heterologous protection against a lethal challenge with Streptococcus pneumoniae in an experimental murine model of pneumonia.在各类传染病中，结核病是全球范围内的首要致死病因，亦是极具威胁的公共卫生挑战，在发展中国家尤为突出。目前临床使用的结核病疫苗卡介苗（Bacillus Calmette-Guerin, BCG），其防护功效不仅与T细胞免疫的特异性诱导密切相关，还可通过被称为‘训练免疫（trained immunity）’的过程，对先天免疫系统细胞实现长期表观遗传与代谢重编程。本研究表明，MTBVAC作为一株减毒活结核分枝杆菌（Mycobacterium tuberculosis）菌株，在成人与新生儿群体中针对结核病抗原展现出良好的安全性与免疫原性；同时该疫苗可通过诱导糖酵解与谷氨酰胺分解过程，并在促炎基因的启动子区域富集组蛋白甲基化标记，从而介导训练免疫效应，使机体在遭遇非相关性细菌刺激的二次攻击时，应答能力得到增强。值得关注的是，上述在人类原代髓系细胞中的研究发现，得到了实验性肺炎小鼠模型的进一步验证：MTBVAC可诱导强效的异源保护作用，使小鼠能够抵御肺炎链球菌（Streptococcus pneumoniae）的致死性攻击。