Mucosal exposure to non-tuberculous mycobacteria elicits B-cell mediated protection against pulmonary tuberculosis

Bacille Calmette Guerin (BCG) is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) disease. However, BCG has limited efficacy, necessitating the development of better vaccines. Non-tuberculous mycobacteria (NTM), a distinct lineage from Mtb, are opportunistic pathogens present in the environment. TB endemic countries experience higher exposure to NTM, but previous studies have not elucidated the relationship between NTM exposure and BCG efficacy. Therefore, we developed a mouse model (BCG+NTM) that mimics human BCG vaccination at an early stage and continuous NTM exposure via the oral route, including during TB infection. Our results show that BCG+NTM mice had improved protection against pulmonary TB correlating with increased pulmonary influx of B-cells, higher titers of anti-Mtb IgA and IgG antibodies in serum and airways, compared to mice vaccinated with BCG alone. Notably, the lungs of BCG+NTM mice developed B-cell aggregates expressing markers of germinal center formation as determined by spatial transcriptomics. We conclude a direct correlation between NTM exposure and protection from TB, with B-cells playing a crucial role. Overall design: This is a spatial transcriptomics dataset generated using 10X Visium kit for FFPE tisues. There are four groups: Saline (control group); BCG (mice vaccinated with Bacille Calmette Geurin vaccine and infected with Mycobacterium tuberculosis); NTM (Mice exposed to 1X10^5 CFU/mL Myobacterium avium via drinking water and infected with Mycobacterium tuberculosis), and BCG+NTM (Mice vaccinated with BCG, exposed to 1X10^5 CFU/mL Myobacterium avium via drinking water and infected with Mycobacterium tuberculosis).

卡介苗（Bacille Calmette Guerin, BCG）是目前唯一获批用于预防结核分枝杆菌（Mycobacterium tuberculosis, Mtb，结核病（TB）的病原菌）感染的疫苗。然而卡介苗的保护效力有限，亟需开发更优的结核疫苗。非结核分枝杆菌（Non-tuberculous mycobacteria, NTM）是一类与结核分枝杆菌演化谱系相异的环境源性机会致病菌。结核病流行国家的人群非结核分枝杆菌暴露率更高，但既往研究尚未阐明非结核分枝杆菌暴露与卡介苗保护效力之间的关联。为此，本研究构建了BCG+NTM小鼠模型，该模型可模拟人类早期卡介苗接种过程，并通过饮水途径实现持续的非结核分枝杆菌暴露（包括结核分枝杆菌感染阶段）。研究结果显示，相较于仅接种卡介苗的小鼠，BCG+NTM模型小鼠对肺结核的保护效力显著提升，该效应与肺部B细胞浸润增多、血清及气道内抗结核分枝杆菌IgA与IgG抗体滴度升高显著相关。值得注意的是，空间转录组学分析证实，BCG+NTM模型小鼠的肺部形成了表达生发中心标志物的B细胞聚集灶。综上，本研究揭示了非结核分枝杆菌暴露与结核病保护效应之间的直接关联，且B细胞在其中发挥关键作用。本数据集为采用10X Visium FFPE组织空间转录组试剂盒构建的空间转录组数据集。实验共设置4组：生理盐水对照组（Saline）；卡介苗组（BCG）：小鼠经卡介苗接种后感染结核分枝杆菌；非结核分枝杆菌组（NTM）：小鼠经饮水暴露于1×10^5 CFU/mL的鸟分枝杆菌（Myobacterium avium）后感染结核分枝杆菌；BCG+NTM组：小鼠经卡介苗接种、饮水暴露于1×10^5 CFU/mL的鸟分枝杆菌（Myobacterium avium）后感染结核分枝杆菌。