01918nas a2200265   4500000000100000008004100001260001200042100001700054700002200071700001600093700001800109700003000127700001800157700002400175700002200199700002200221700002100243700001400264700002900278245012700307856005500434300001300489490000700502520114300509       2026                            d  c2026-011 aChak Hon Luk1 aGabriel L. Conway1 aKim Jee Goh1 aAntony Fearns1 aIrene Rodriguez Hernandez1 aNathan J. Day1 aNatalia Athanasiadi1 aRocco D’Antuono1 aEnrica Pellegrino1 aJanick D. Stucki1 aNina Hobi1 aMaximiliano G. Gutierrez00aAutologous human iPSC–derived alveolus-on-chip reveals early pathological events of Mycobacterium tuberculosis infection  uhttps://www.science.org/doi/10.1126/sciadv.aea9874  aeaea98740 v123 aImmunocompetent and experimentally accessible alveolar systems to study human respiratory diseases are lacking. Here, we developed a single-donor human induced pluripotent stem cell-derived lung-on-chip (iLoC) containing type II and I alveolar epithelial cells, vascular endothelial cells, and macrophages in a microfluidic device that mimic lung three-dimensional mechanical stretching and air-liquid interface. Imaging and single-cell RNA sequencing analysis revealed that the iLoC recapitulated cellular profiles present in the human distal lung. Infection of the iLoC with the human pathogen Mycobacterium tuberculosis (Mtb) showed that both macrophages and epithelial cells were infected but not permissive to bacterial replication. Stochastically, large macrophage clusters containing necrotic macrophages supporting Mtb replication were observed. A genetically engineered autophagy-deficient iLoC revealed that after Mtb infection, macrophage necrosis was higher upon ATG14 deficiency without bacterial replication. Together, we report an autologous, genetically tractable human alveolar model to study lung diseases and therapies.