Mechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip

Haiqing Bai, Longlong Si, Amanda Jiang, Chaitra Belgur, Yunhao Zhai, Roberto Plebani, Crystal Yuri Oh, Melissa Rodas, Aditya Patil, Atiq Nurani, Sarah E. Gilpin, Rani K. Powers, Girija Goyal, Rachelle Prantil-Baun and Donald E. Ingber ()
Additional contact information
Haiqing Bai: Harvard University
Longlong Si: Harvard University
Amanda Jiang: Harvard University
Chaitra Belgur: Harvard University
Yunhao Zhai: Harvard University
Roberto Plebani: Harvard University
Crystal Yuri Oh: Harvard University
Melissa Rodas: Harvard University
Aditya Patil: Harvard University
Atiq Nurani: Harvard University
Sarah E. Gilpin: Harvard University
Rani K. Powers: Harvard University
Girija Goyal: Harvard University
Rachelle Prantil-Baun: Harvard University
Donald E. Ingber: Harvard University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Mechanical 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.

Date: 2022
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DOI: 10.1038/s41467-022-29562-4

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