Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics

Longlong Si; Haiqing Bai; Melissa Rodas; Wuji Cao; Crystal Yur Oh; Amanda Jiang; Atiq Nurani; Danni Y Zhu; Girija Goyal; Sarah Gilpin; Rachelle Prantil-Baun; Donald E. Ingber

The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.13.039917 doi: bioRxiv preprint channel of the microfluidic chip to mimic in vivo infection with airborne influenza (Fig. 1A ), real-time fluorescence microscopic analysis confirmed that the virus infected the human airway epithelial cells (Fig. 1B, Supplementary Movie 1) , and this was accompanied by damage to the epithelium, including disruption of tight junctions, loss of apical cilia (Fig. 1B) and compromised barrier function (Fig. 1G) . Significantly less infection was detected in undifferentiated airway basal epithelium prior to culture at an ALI on-chip, and there was no detectable direct infection of the endothelium by the virus (Fig. S2A) . Interestingly, however, influenza infection led to disruption of the lung endothelium on-chip, as evidenced by loss of VE-cadherin containing adherens junctions (Fig. 1B) (10 3 -to 10 4 -fold) increases in viral titers over 24 to 48 hours in highly differentiated human lung airway epithelium on-chip ( Fig. 2A) . Notably, the H3N2 virus strains (HK/68 and Pan/99) exhibited ~10-fold greater replication efficiency than the H1N1 virus strains (PR8, WSN, and NL/09) ( Fig. 2A) and caused more barrier function damage (Fig. 1G) and cilia loss (Fig. S2B) , which replicates the finding that H3N2 is more infectious and virulent, and causes more severe clinical symptoms in humans 16 . Donor-to-donor variability was minimal in these studies in terms of sensitivity to influenza infection, as author/funder. All rights reserved. No reuse allowed without permission.