Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA.
mBio. 2019 May 7;10(3):e00723-19. doi: 10.1128/mBio.00723-19.
Infectious viruses so precisely fit their hosts that the study of natural viral infection depends on host-specific mechanisms that affect viral infection. For human parainfluenza virus 3, a prevalent cause of lower respiratory tract disease in infants, circulating human viruses are genetically different from viruses grown in standard laboratory conditions; the surface glycoproteins that mediate host cell entry on circulating viruses are suited to the environment of the human lung and differ from those of viruses grown in cultured cells. Polarized human airway epithelium cultures have been used to represent the large, proximal airways of mature adult airways. Here we modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids derived from human pluripotent stem cells contain mesoderm and pulmonary endoderm and develop into branching airway and alveolar structures. Whole-genome sequencing analysis of parainfluenza viruses replicating in the organoids showed maintenance of nucleotide identity, suggesting that no selective pressure is exerted on the virus in this tissue. Infection with parainfluenza virus led to viral shedding without morphological changes, while respiratory syncytial virus infection induced detachment and shedding of infected cells into the lung organoid lumens, reminiscent of parainfluenza and respiratory syncytial virus in human infant lungs. Measles virus infection, in contrast, induced syncytium formation. These human stem cell-derived lung organoids may serve as an authentic model for respiratory viral pathogenesis in the developing or infant lung, recapitulating respiratory viral infection in the host. Respiratory viruses are among the first pathogens encountered by young children, and the significant impact of these viral infections on the developing lung is poorly understood. Circulating viruses are suited to the environment of the human lung and are different from those of viruses grown in cultured cells. We modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids, derived from human pluripotent stem cells, develop into branching airway and alveolar structures and provide a tissue environment that maintains the authentic viral genome. The lung organoids can be genetically engineered prior to differentiation, thereby generating tissues bearing or lacking specific features that may be relevant to viral infection, a feature that may have utility for the study of host-pathogen interaction for a range of lung pathogens.
感染性病毒与宿主的匹配非常精确，以至于对自然病毒感染的研究依赖于影响病毒感染的宿主特异性机制。对于副流感病毒 3 型，它是婴儿下呼吸道疾病的常见病因，循环中的人类病毒在遗传上与在标准实验室条件下生长的病毒不同；介导循环病毒进入宿主细胞的表面糖蛋白适应人类肺部的环境，与在培养细胞中生长的病毒不同。极化的人呼吸道上皮细胞培养物已被用于代表成熟成人气道的大近端气道。在这里，我们使用代表整个发育中婴儿肺的肺类器官来模拟发生在儿童中的呼吸道病毒感染或感染远端肺的呼吸道病毒感染。这些源自人多能干细胞的 3D 肺类器官包含中胚层和肺内胚层，并发育成分支气道和肺泡结构。对在类器官中复制的副流感病毒进行全基因组测序分析表明，核苷酸同一性得到维持，这表明该组织中病毒没有受到选择压力。副流感病毒感染导致病毒脱落而没有形态变化，而呼吸道合胞病毒感染导致感染细胞脱离并脱落到肺类器官腔中，使人联想到人婴儿肺中的副流感病毒和呼吸道合胞病毒。相比之下，麻疹病毒感染诱导合胞体形成。这些人干细胞衍生的肺类器官可以作为发育中或婴儿肺的呼吸道病毒发病机制的真实模型，在宿主中再现呼吸道病毒感染。呼吸道病毒是幼儿最早遇到的病原体之一，这些病毒感染对发育中肺的重大影响尚未得到充分了解。循环中的病毒适应人类肺部的环境，与在培养细胞中生长的病毒不同。我们使用代表整个发育中婴儿肺的肺类器官来模拟发生在儿童中的呼吸道病毒感染或感染远端肺的呼吸道病毒感染。这些源自人多能干细胞的 3D 肺类器官发育成分支气道和肺泡结构，并提供维持真实病毒基因组的组织环境。肺类器官可以在分化前进行基因工程，从而生成具有或缺乏可能与病毒感染相关的特定特征的组织，这一特征对于一系列肺部病原体的宿主-病原体相互作用研究可能具有实用性。
