GSE171711
A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics
The rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here, we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production, and the recruitment of circulating immune cells. In chips infected with pseudotyped SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection, but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential. Overall design: Independent biological triplicates of transformed lung alveolar (A549) transduced with a vector expressing human ACE2 were pre-treated with amodiaquine (10 µM) for 1hr before SARS-CoV-2 infection (USA-WA1/2020, MOI: 0.1); 24hrs post infection samples were examined by mRNA-sequencing. Additionally, Syrian golden hamsters were treated with amodiaquine (75mg/kg) by oral gavage one day before SARS-CoV-2 infection (100 PFU), on the day of infection, and one and 2 days after infection. The animals were sacrificed and lungs harvested for mRNA-sequencing on day 3 post infection.