02264nas a2200373   4500000000100000000000100001008004100002260001500043653002800058653002000086653002300106653002000129100001600149700001600165700001700181700001900198700001600217700002000233700002000253700001800273700001700291700001600308700002000324700001900344700001700363700002600380700002100406245011300427856005500540300000900595490000700604520126500611022001401876       2022                            d  c2022-04-0810aAntimicrobial responses10aInnate immunity10aTissue engineering10aViral infection1 aHaiqing Bai1 aLonglong Si1 aAmanda Jiang1 aChaitra Belgur1 aYunhao Zhai1 aRoberto Plebani1 aCrystal Yuri Oh1 aMelissa Rodas1 aAditya Patil1 aAtiq Nurani1 aSarah E. Gilpin1 aRani K. Powers1 aGirija Goyal1 aRachelle Prantil-Baun1 aDonald E. Ingber00aMechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip  uhttps://www.nature.com/articles/s41467-022-29562-4  a19280 v133 aMechanical breathing motions have a fundamental function in lung development and disease, but little is known about how they contribute to host innate immunity. Here we use a human lung alveolus chip that experiences cyclic breathing-like deformations to investigate whether physical forces influence innate immune responses to viral infection. Influenza H3N2 infection of mechanically active chips induces a cascade of host responses including increased lung permeability, apoptosis, cell regeneration, cytokines production, and recruitment of circulating immune cells. Comparison with static chips reveals that breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells, which are mediated in part through activation of the mechanosensitive ion channel TRPV4 and signaling via receptor for advanced glycation end products (RAGE). RAGE inhibitors suppress cytokines induction, while TRPV4 inhibition attenuates both inflammation and viral burden, in infected chips with breathing motions. Therefore, TRPV4 and RAGE may serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation.  a2041-1723