Discovery of influenza drug resistance mutations and host therapeutic targets using a human airway chip

Here we demonstrate that influenza virus replication, host responses to infection, evolution through mutation or gene reassortment, and clinical efficacy of antiviral drugs can be reconstituted in a human Airway Chip microfluidic culture device. Modeling human-to-human transmission of infection in the continued presence of antiviral drugs on chips led to the emergence of clinically prevalent mutations responsible for amantadine- and oseltamivir-resistance, as well as the discovery of new resistance mutations. Analysis of infection responses resulted in identification of host therapeutic targets and demonstration that existing non-antiviral drugs may be repurposed to inhibit viral replication and synergize with antiviral therapeutics by targeting the host response to infection rather than the virus itself. This Influenza Chip may represent an alternative preclinical tool for development of new antiviral drugs and vaccines.One Sentence SummaryNew drug resistance mutations and potential tolerance-inducing therapeutics were discovered using an organ chip model of influenza infection.