Tuberculosis, one of the oldest human pathogens remains a major global health threat. Recent advances in organoid technology offer a unique opportunity to grow different human organs in vitro, including the human airway, that faithfully recapitulate tissue architecture and function. We have explored the potential of human airway organoids (AOs) as a novel system in which to model tuberculosis infection. To this end, we adapted biosafety containment level 3 approved procedures to allow successful microinjection of Mycobacterium tuberculosis, the causative agent of tuberculosis, into AOs. We reveal that mycobacteria infected epithelial cells with low efficiency, and that the organoid microenvironment was able to control, but not eliminate the pathogen. We demonstrate that AOs responded to infection by inducing cytokine and antimicrobial peptide production, and inhibiting mucins. Given the importance of myeloid cells in tuberculosis infection, we cocultured mycobacteria-infected organoids with human monocyte-derived macrophages, and found that these cells were recruited to the organoid epithelium. We conclude that adult stem cell-derived airway organoids can be used to model early events of tuberculosis infection and offer new avenues for fundamental and therapeutic research.

中文翻译：

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人支气管气道类器官中的分枝杆菌-宿主相互作用

结核病是人类最古老的病原体之一，仍然是全球健康的主要威胁。类器官技术的最新进展为在体外忠实地概述组织结构和功能的包括人体呼吸道在内的各种人体器官提供了独特的机会。我们已经探索了人类气道类器官（AOs）作为模拟结核感染的新型系统的潜力。为此，我们采用了生物安全控制等级3的批准程序，以允许将结核病的致病因子结核分枝杆菌成功显微注射到AO中。我们发现分枝杆菌感染上皮细胞的效率低下，并且类器官微环境能够控制但不能消除病原体。我们证明了AOs通过诱导细胞因子和抗菌肽的产生，并抑制粘蛋白对感染作出反应。考虑到髓样细胞在结核感染中的重要性，我们将分枝杆菌感染的类器官与人类单核细胞衍生的巨噬细胞共培养，并发现这些细胞被募集到类器官上皮中。我们得出的结论是，成人干细胞来源的气道类器官可用于模拟结核感染的早期事件，并为基础和治疗研究提供新途径。