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BCG誘導(dǎo)肺部噬細(xì)胞活化并提供對結(jié)核病的長期??保護(hù)

發(fā)表日期：2021-09-28

BCG trains lung macrophages

Bacillus Calmette-Guerin (BCG) is an attenuated mycobacterial vaccine historically used to protect against Mycobacterium tuberculosis (Mtb), and intradermal BCG vaccination has modest efficacy. Mata et al. now define immune mechanisms associated with protection induced by pulmonary BCG administration. They observed that mice vaccinated with BCG via pulmonary delivery were able to limit early dissemination of Mtb upon challenge. Long-term protection was also observed and was linked to BCG-mediated activation of alveolar macrophages (AMs) that were rapidly reactivated upon challenge, suggesting a role for trained immunity. These results highlight the potential of intrapulmonary BCG challenge and the role of AMs in protection against Mtb.

卡介苗 (BCG) 是一種減毒分枝桿菌疫苗，歷史上用于預(yù)防結(jié)核分枝桿菌( Mtb )，皮內(nèi)注射 BCG 疫苗具有中等功效?，F(xiàn)在定義與肺 BCG 給藥誘導(dǎo)的保護(hù)相關(guān)的免疫機(jī)制。他們觀察到，通過肺部遞送接種 BCG 的小鼠能夠限制Mtb在受到攻擊時的早期傳播。還觀察到了長期保護(hù)，并且與 BCG 介導(dǎo)的肺泡巨噬細(xì)胞 (AM) 激活有關(guān)，這些巨噬細(xì)胞在受到攻擊時會迅速重新激活，這表明訓(xùn)練免疫的作用。這些結(jié)果突出了肺內(nèi) BCG 挑戰(zhàn)的潛力和 AMs 在預(yù)防結(jié)核桿菌。

Abstract

Bacillus Calmette-Guerin (BCG) is an attenuated bacterial vaccine used to protect against Mycobacterium tuberculosis (Mtb) in regions where infections are highly prevalent. BCG is currently delivered by the intradermal route, but alternative routes of administration are of great interest, including intrapulmonary delivery to more closely mimic respiratory Mtb infection. In this study, mice subjected to pulmonary delivery of green fluorescent protein–tagged strains of virulent (Mtb) and attenuated (BCG) mycobacteria were studied to better characterize infected lung cell subsets. Profound differences in dissemination patterns were detected between Mtb and BCG, with a strong tendency of Mtb to disseminate from alveolar macrophages (AMs) to other myeloid subsets, mainly neutrophils and recruited macrophages. BCG mostly remained in AMs, which promoted their activation. These preactivated macrophages were highly efficient in containing Mtb bacilli upon challenge and disrupting early bacterial dissemination, which suggests a potential mechanism of protection associated with pulmonary BCG vaccination. Respiratory BCG also protected mice against a lethal Streptococcus pneumoniae challenge, suggesting that BCG-induced innate activation could confer heterologous protection against respiratory pathogens different from Mtb. BCG drove long-term activation of AMs, even after vaccine clearance, and these AMs reacted efficiently upon subsequent challenge. These results suggest the generation of a trained innate memory-like response in AMs induced by pulmonary BCG vaccination.

卡介苗 (BCG) 是一種減毒細(xì)菌疫苗，用于在感染高度流行的地區(qū)預(yù)防結(jié)核分枝桿菌( Mtb )。BCG 目前通過皮內(nèi)途徑遞送，但其他給藥途徑引起了極大的興趣，包括肺內(nèi)遞送以更接近地模擬呼吸道Mtb感染。在這項(xiàng)研究中，對經(jīng)過綠色熒光蛋白標(biāo)記的有毒 ( Mtb ) 和減毒 (BCG) 分枝桿菌菌株進(jìn)行肺部遞送的小鼠進(jìn)行了研究，以更好地表征受感染的肺細(xì)胞亞群。之間檢測到在傳播模式深刻分歧的Mtb和BCG，具有的強(qiáng)烈傾向的Mtb從肺泡巨噬細(xì)胞 (AMs) 傳播到其他髓系亞群，主要是中性粒細(xì)胞和募集的巨噬細(xì)胞。BCG 主要保留在 AMs 中，這促進(jìn)了它們的激活。這些預(yù)活化的巨噬細(xì)胞在攻擊后能非常有效地包含Mtb桿菌并破壞早期細(xì)菌傳播，這表明與肺 BCG 疫苗接種相關(guān)的潛在保護(hù)機(jī)制。呼吸道 BCG 還保護(hù)小鼠免受致命性肺炎鏈球菌的攻擊，這表明 BCG 誘導(dǎo)的先天激活可以賦予與Mtb不同的呼吸道病原體的異源保護(hù). 即使在疫苗清除后，BCG 也能驅(qū)動 AMs 的長期激活，并且這些 AMs 在隨后的挑戰(zhàn)中做出有效反應(yīng)。這些結(jié)果表明在肺 BCG 疫苗接種誘導(dǎo)的 AM 中產(chǎn)生了訓(xùn)練有素的先天記憶樣反應(yīng)。