03528nas a2200469   4500000000100000000000100001008004100002260001500043653001000058653001000068653003100078653001100109653000900120653002800129653002600157653002900183653002200212653001900234653001900253653002100272653001000293653003100303653003300334653001400367653001700381653002400398100001800422700002600440700002700466700003100493700002600524700003400550700002900584700002000613700001600633700002100649245012600670300001300796490000700809520222800816022001403044       2022                            d  c2022-06-2910aAdult10aChild10aHuman Embryonic Stem Cells10aHumans10aLung10aPneumococcal Infections10aPneumococcal Vaccines10aStreptococcus pneumoniae10aVirulence Factors10aalveolar cells10abiosurfactants10adisease modeling10ahESCs10aHuman Embryonic Stem Cells10ahuman pluripotent stem cells10aminilungs10apneumococcus10asurfactant proteins1 aJulio Sempere1 aSuélen Andreia Rossi1 aIrene Chamorro-Herrero1 aFernando González-Camacho1 aMaría Pilar de Lucas1 aJosé María Rojas-Cabañeros1 aCarlos Pelleschi Taborda1 aÓscar Zaragoza1 aJosé Yuste1 aAlberto Zambrano00aMinilungs from Human Embryonic Stem Cells to Study the Interaction of Streptococcus pneumoniae with the Respiratory Tract  ae00453220 v103 aThe 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.  a2165-0497