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

to the site of infection in the airway epithelium contributes significantly to influenza pathogenesis in the lung 17 ; however, this cannot be studied easily in existing preclinical models. When primary human neutrophils were perfused through the vascular channel of Airway Chips infected with H1N1 or H3N2, we observed recruitment of these circulating immune cells to the apical surface of the activated lung endothelium within minutes ( Fig. 2B top, Supplementary Movie 2) . This was followed by transmigration of the neutrophils through the endothelium and the ECM-coated pores of the intervening membrane, and up into the airway epithelium over hours (Fig. 2B bottom) . The neutrophils targeted the influenza nucleoprotein (NP)-positive infected airway cells (Fig. S3 ) and induced them to coalesce into clusters that decreased in size over time, resulting in clearance of the viruses, as evidenced by the disappearance of GFPpositive cells over a period of 1-2 days (Fig. 2B bottom) . Consistent with the ability of H3N2 virus to induce stronger inflammation relative to H1N1 in vivo 16 , H3N2 also stimulated more neutrophil recruitment than H1N1 on-chip (Fig. 2C) , and neutrophil infiltration into the epithelium significantly decreased the viral titers of both H1N1 and H3N2 on-chip (Fig. 2D) , consistent with the protective role that neutrophils provide by clearing virus in vivo 17 . H1N1 infection also was accompanied by increased secretion of various inflammatory cytokines and chemokines, including IL-6, IP-10, RANTES, interferon-β, and MCP-1, which could easily be measured in the effluent from the vascular channel (Fig. 2E) . author/funder. All rights reserved. No reuse allowed without permission.