02392nas a2200385   4500000000100000000000100001008004100002260001500043653002700058653002000085653002300105100002100128700001800149700002400167700001900191700001400210700001500224700001700239700001800256700001600274700001600290700001800306700001800324700001700342700002100359700001900380700002000399700001600419700001900435245009900454856005500553300000900608520137500617022001401992       2025                            d  c2025-09-2310aBiomedical Engineering10aInfluenza virus10aTissue engineering1 aRachel Ringquist1 aEshant Bhatia1 aParamita Chatterjee1 aDrishti Maniar1 aZhou Fang1 aPage Franz1 aLiana Kramer1 aDelta Ghoshal1 aNeha Sonthi1 aEmma Downey1 aJoshua Canlas1 aAbigail Ochal1 aSavi Agarwal1 aValeria Cuéllar1 aGrace Harrigan1 aAhmet F. Coskun1 aAnkur Singh1 aKrishnendu Roy00aAn immune-competent lung-on-a-chip for modelling the human severe influenza infection response  uhttps://www.nature.com/articles/s41551-025-01491-9  a1-233 aSevere influenza affects 3–5 million people worldwide each year, resulting in more than 300,000 deaths annually. However, standard-of-care antiviral therapeutics have limited effectiveness in these patients. Current preclinical models of severe influenza fail to accurately recapitulate the human immune response to severe viral infection. Here we develop an immune-competent, microvascularized, human lung-on-a-chip device to model the small airways, successfully demonstrating the cytokine storm, immune cell activation, epithelial cell damage, and other cellular- and tissue-level human immune responses to severe H1N1 infection. We find that interleukin-1β and tumour necrosis factor-α play opposing roles in the initiation and regulation of the cytokine storm associated with severe influenza. Furthermore, we discover the critical stromal–immune CXCL12–CXCR4 interaction and its role in immune response to infection. Our results underscore the importance of stromal cells and immune cells in microphysiological models of severe lung disease, describing a scalable model for severe influenza research. We expect the immune-competent human lung-on-a-chip device to enable critical discoveries in respiratory host–pathogen interactions, therapeutic side effects, vaccine potency evaluation, and crosstalk between systemic and mucosal immunity in human lung.  a2157-846X