Biotechnology of Stem Cells and Organoids, Chronic Diseases Program, Instituto de Salud Carlos IIIgrid.413448.e, Madrid, Spain.
Spanish Pneumococcal Reference Laboratory, Centro Nacional de Microbiología, and CIBER of Respiratory Diseases (CIBERES), Instituto de Salud Carlos IIIgrid.413448.e, Madrid, Spain.
Microbiol Spectr. 2022 Jun 29;10(3):e0045322. doi: 10.1128/spectrum.00453-22. Epub 2022 Jun 13.
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. 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.
新一代源自人类多能干细胞的类器官为宿主-细菌相互作用研究提供了一种很有前途的策略。类器官再现了组成、细胞类型的多样性，并且在某种程度上再现了天然器官的功能特征。我们从人类胚胎干细胞中生成了肺芽类器官，以研究肺炎链球菌（肺炎球菌）与肺泡上皮的相互作用。侵袭性肺炎球菌病是一个重要的健康问题，可能是由于肺炎球菌从下呼吸道传播到无菌部位引起的。我们在这里展示了一种有效的实验方法来模拟发生在人类肺部的肺炎球菌感染的主要事件，探索细菌与上皮的黏附、内化以及触发先天反应，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，这种基于人小型肺的模型可用于研究肺炎球菌毒力因子和不同血清型的发病机制，并可在可靠的人类环境中进行治疗干预。肺炎链球菌在全球范围内导致高发病率和死亡率，主要影响儿童和 65 岁以上的成年人。肺炎球菌也是细菌性肺炎和非流行型脑膜炎的最常见病原体，也是细菌性败血症的常见病因。尽管肺炎球菌疫苗的引入降低了肺炎球菌病的负担，但抗生素耐药株和非疫苗型通过血清型替代的出现令人担忧。为了研究肺炎球菌的生物学并建立肺炎球菌发病机制的可靠人类模型，我们从胚胎干细胞中生成了人小型肺。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，如黏附、内化和初始肺泡先天反应。该模型还代表了研究参与肺炎的毒力因子、药物筛选和其他治疗干预的绝佳替代方法。
