PDF(Pubmed)
Abstract：
The new generation of organoids derived from human pluripotent stem cells holds a promising strategy for modeling host-bacteria interaction studies. Organoids recapitulate the composition, diversity of cell types, and, to some extent, the functional features of the native organ. We generated lung bud organoids derived from human embryonic stem cells to study the interaction of Streptococcus pneumoniae (pneumococcus) with the alveolar epithelium. Invasive pneumococcal disease is an important health problem that may occur as a result of the spread of pneumococcus from the lower respiratory tract to sterile sites. We show here an efficient experimental approach to model the main events of the pneumococcal infection that occur in the human lung, exploring bacterial adherence to the epithelium and internalization and triggering an innate response that includes the interaction with surfactant and the expression of representative cytokines and chemokines. Thus, this model, based on human minilungs, can be used to study pneumococcal virulence factors and the pathogenesis of different serotypes, and it will allow therapeutic interventions in a reliable human context. IMPORTANCE Streptococcus pneumoniae is responsible for high morbidity and mortalities rates worldwide, affecting mainly children and adults older than 65 years. Pneumococcus is also the most common etiologic agent of bacterial pneumonia and nonepidemic meningitis, and it is a frequent cause of bacterial sepsis. Although the introduction of pneumococcal vaccines has decreased the burden of pneumococcal disease, the rise of antibiotic-resistant strains and nonvaccine types by serotype replacement is worrisome. To study the biology of pneumococcus and to establish a reliable human model for pneumococcal pathogenesis, we generated human minilungs from embryonic stem cells. The results show that these organoids can be used to model some events occurring during the interaction of pneumococcus with the lung, such as adherence, internalization, and the initial alveolar innate response. This model also represents a great alternative for studying virulence factors involved in pneumonia, drug screening, and other therapeutic interventions.
摘要：
来自人类多能干细胞的新一代类器官为宿主-细菌相互作用研究建模提供了有希望的策略。类器官概括了组合物，细胞类型的多样性，and,在某种程度上,天然器官的功能特征。我们从人类胚胎干细胞中产生了肺芽类器官，以研究肺炎链球菌（肺炎球菌）与肺泡上皮的相互作用。侵袭性肺炎球菌疾病是重要的健康问题，可能是肺炎球菌从下呼吸道传播到无菌部位的结果。我们在这里展示了一种有效的实验方法来模拟在人肺中发生的肺炎球菌感染的主要事件，探索细菌对上皮的粘附和内化，并触发先天反应，包括与表面活性剂的相互作用以及代表性细胞因子和趋化因子的表达。因此，这个模型,基于人类的微升，可用于研究肺炎球菌毒力因子和不同血清型的发病机制,它将允许在可靠的人类背景下进行治疗干预。重要性肺炎链球菌是全球高发病率和死亡率的原因，主要影响65岁以上的儿童和成人。肺炎球菌也是细菌性肺炎和非流行性脑膜炎的最常见病原体，它是细菌性败血症的常见原因。尽管肺炎球菌疫苗的引入减轻了肺炎球菌疾病的负担，血清型替代导致抗生素耐药菌株和非疫苗类型的增加令人担忧.目的研究肺炎球菌的生物学特性,建立可靠的肺炎球菌发病模型,我们从胚胎干细胞中产生了人类微枝。结果表明，这些类器官可用于模拟肺炎球菌与肺相互作用过程中发生的一些事件，如坚持，内化，和最初的肺泡先天反应。该模型也代表了研究肺炎毒力因子的一个很好的替代方法，药物筛选,和其他治疗干预措施。
