Mechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 08, 2022
- Source ID
- 10.1038/s41467-022-29562-4
Entities
People
- Aditya Patil
- Amanda Jiang
- Atiq Nurani
- Chaitra Belgur
- Crystal Yuri Oh
- Donald E. Ingber
- Girija Goyal
- Haiqing Bai
- Longlong Si
- Melissa Rodas
- Rachelle Prantil-baun
- Rani K. Powers
- Roberto Plebani
- Sarah E. Gilpin
- Yunhao Zhai
Organizations
- Harvard University
- National Heart, Lung, and Blood Institute
- United States Department of Defense
- United States Department of Health and Human Services