The Public Health Research Institute at New Jersey Medical School, Rutgers University, Newark, NJ, 07103, USA.
Department of Pulmonary, Allergy, and Critical Care Medicine, The University of Alabama at Birmingham, Birmingham, AL35294, USA.
Commun Biol. 2021 Nov 3;4(1):1256. doi: 10.1038/s42003-021-02769-9.
In vitro phagocytosis of Mycobacterium tuberculosis (Mtb) aggregates (Mtb-AG), rather than similar numbers of single bacilli (Mtb-SC), induces host macrophage death and favors bacterial growth. Here, we examined whether aggregation contributes to enhanced Mtb pathogenicity in vivo in rabbit lungs. Rabbits were exposed to infectious aerosols containing mainly Mtb-AG or Mtb-SC. The lung bacterial load, systemic immune response, histology, and immune cell composition were investigated over time. Genome-wide transcriptome analysis, cellular and tissue-level assays, and immunofluorescent imaging were performed on lung tissue to define and compare immune activation and pathogenesis between Mtb-AG and Mtb-SC infection. Lung bacillary loads, disease scores, lesion size, and structure were significantly higher in Mtb-AG than Mtb-SC infected animals. Differences in immune cell distribution and activation were noted in the lungs of the two groups of infected animals. Consistently larger lung granulomas with large aggregates of Mtb, extensive necrotic foci, and elevated matrix metalloproteases expression were observed in Mtb-AG infected rabbits. Our findings suggest that bacillary aggregation increases Mtb fitness for improved growth and accelerates lung inflammation and infected host cell death, thereby exacerbating disease pathology in the lungs.
结核分枝杆菌（Mtb）聚集体（Mtb-AG）的体外吞噬作用，而非相同数量的单个杆菌（Mtb-SC），会诱导宿主巨噬细胞死亡并有利于细菌生长。在此，我们研究了聚集作用是否会促进兔肺中体内增强的 Mtb 致病性。将兔子暴露于含有主要 Mtb-AG 或 Mtb-SC 的感染性气溶胶中。随着时间的推移，研究了肺部细菌负荷、全身免疫反应、组织学和免疫细胞组成。对肺组织进行全基因组转录组分析、细胞和组织水平检测以及免疫荧光成像，以定义和比较 Mtb-AG 和 Mtb-SC 感染之间的免疫激活和发病机制。Mtb-AG 感染动物的肺部细菌负荷、疾病评分、病变大小和结构明显高于 Mtb-SC 感染动物。在两组感染动物的肺部观察到免疫细胞分布和激活的差异。在 Mtb-AG 感染的兔子中，观察到更大的肺部肉芽肿，其中含有大量 Mtb 聚集物、广泛的坏死灶和基质金属蛋白酶表达升高。我们的研究结果表明，细菌聚集增加了 Mtb 的适应性，从而促进了生长，并加速了肺部炎症和受感染宿主细胞的死亡，从而加剧了肺部的疾病病理学。
