Departamento de Genética, Ecologia e Evolução, Programa de Pós-Graduação em Genética, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Departamento de Bioquímica e Imunologia, Programa de Pós-Graduação em Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
J Immunol. 2023 Sep 1;211(5):791-803. doi: 10.4049/jimmunol.2200642.
The bacillus Calmette-Guérin (BCG) can elicit enhanced innate immune responses against a wide range of infections, known as trained immunity. Brucella abortus is the causative agent of brucellosis, a debilitating disease that affects humans and animals. In this study, we demonstrate that C57BL/6 mouse bone marrow-derived macrophages under BCG training enhance inflammatory responses against B. abortus. BCG-trained macrophages showed increased MHC class II and CD40 expression on the cell surface and higher IL-6, IL-12, and IL-1β production. The increase in IL-1β secretion was accompanied by enhanced activation of canonical and noncanonical inflammasome platforms. We observed elevated caspase-11 expression and caspase-1 processing in BCG-trained macrophages in response to B. abortus compared with untrained cells. In addition, these BCG-trained cells showed higher NLRP3 expression after B. abortus infection. From a metabolic point of view, signaling through the Akt/mammalian target of rapamycin/S6 kinase pathway was also enhanced. In addition, BCG training resulted in higher inducible NO synthase expression and nitrite production, culminating in an improved macrophage-killing capacity against intracellular B. abortus. In vivo, we monitored a significant reduction in the bacterial burden in organs from BCG-trained C57BL/6 mice when compared with the untrained group. In addition, previous BCG immunization of RAG-1-deficient mice partially protects against Brucella infection, suggesting the important role of the innate immune compartment in this scenario. Furthermore, naive recipient mice that received BM transfer from BCG-trained donors showed greater resistance to B. abortus when compared with their untrained counterparts. These results demonstrate that BCG-induced trained immunity in mice results in better control of intracellular B. abortus in vivo and in vitro.
卡介苗（BCG）可引发针对广泛感染的增强固有免疫反应，这种反应被称为训练免疫。布鲁氏菌属流产种是布鲁氏菌病的病原体，这是一种影响人类和动物的衰弱性疾病。在这项研究中，我们证明了经 BCG 训练的 C57BL/6 小鼠骨髓来源的巨噬细胞增强了对流产布鲁氏菌的炎症反应。BCG 训练的巨噬细胞在细胞表面上表现出更高的 MHC Ⅱ类和 CD40 表达以及更高的 IL-6、IL-12 和 IL-1β 产生。IL-1β 分泌的增加伴随着经典和非经典炎症小体平台的增强激活。与未训练的细胞相比，我们观察到在 BCG 训练的巨噬细胞中，在受到流产布鲁氏菌的刺激时，半胱天冬酶-11 的表达和半胱天冬酶-1 的加工增加。此外，这些 BCG 训练的细胞在感染流产布鲁氏菌后表现出更高的 NLRP3 表达。从代谢的角度来看，通过 Akt/哺乳动物雷帕霉素靶蛋白/S6 激酶途径的信号也得到了增强。此外，BCG 训练导致诱导型一氧化氮合酶表达和亚硝酸盐产生增加，最终导致对细胞内流产布鲁氏菌的杀伤能力提高。在体内，与未训练组相比，我们监测到经 BCG 训练的 C57BL/6 小鼠器官中的细菌负荷显著降低。此外，RAG-1 缺陷型小鼠的先前 BCG 免疫接种部分保护其免受布鲁氏菌感染，这表明固有免疫成分在这种情况下发挥了重要作用。此外，与未训练的对照组相比，从 BCG 训练的供体接受 BM 转移的幼稚受体小鼠对流产布鲁氏菌表现出更大的抵抗力。这些结果表明，BCG 诱导的小鼠训练免疫导致更好地控制体内流产布鲁氏菌。
