Department of Microbiology, Faculty of Medicine, University of Zaragoza, Zaragoza, Spain.
CIBERES and Research Network on Respiratory Diseases, Spanish Ministry of Health and Instituto de Salud Carlos III, Madrid, Spain.
PLoS Pathog. 2020 Apr 2;16(4):e1008404. doi: 10.1371/journal.ppat.1008404. eCollection 2020 Apr.
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.
在传染病中，结核病是全球范围内导致死亡的主要原因，尤其是在发展中国家，它构成了严重威胁。卡介苗（BCG）是目前预防结核病的疫苗，其保护作用不仅与特定的 T 细胞免疫诱导有关，还与固有免疫系统的细胞通过一种称为训练免疫的过程进行长期的表观遗传和代谢重编程有关。在这里，我们证明了 MTBVAC，一种减毒的结核分枝杆菌菌株，在成人和新生儿中对结核抗原既安全又具有免疫原性，它还能够通过诱导糖酵解和谷氨酰胺分解以及在促炎基因启动子处积累组蛋白甲基化标记来产生训练免疫，从而促进在受到非相关细菌刺激物的二次挑战后产生增强的反应。重要的是，这些在人类原代髓样细胞中的发现，在肺炎实验小鼠模型中得到了强有力的补充，MTBVAC 可强烈诱导针对肺炎链球菌的致死性攻击的异源保护。
