A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics

Abstract

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 airway chips infected with influenza A, the co-administration of nafamostat with oseltamivir doubled the treatment-time window for oseltamivir. In chips infected with pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-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.

Enteric coronavirus infection and treatment modeled with an immunocompetent human intestine-on-a-chip

“…2A). While the presence of endothelium was shown to influence influenza virus infection in Lung Airway Chips in past studies 2,20,21 , the presence of endothelium did not significantly alter infection of intestinal epithelium by NL63 (Supp. Fig.…”

“…CoV-2, in vitro 8,9,42,43 . However, the physical microenvironment of Organ chips (e.g., fluid flow, cyclic peristalsis-like mechanical deformations) has been previously shown to have potent effects on cell differentiation and function that are crucial for recapitulation of complex organ level physiology and pathophysiology with high fidelity 2,44,45 . This also seems to be the case here given that the same organoid-derived cells were cultured in the same medium in the different models, yet their phenotype differed greatly.…”

Three-Dimensional Cell Cultures as a Research Platform in Lung Diseases and COVID-19

“…The main treatments for COVID-19 consist of palliative and supportive care. Several clinical trials have been conducted to repurpose or reposition existing drugs for COVID-19 [35,36]. From a pharmacological perspective, this is a remarkably interesting approach because it reduces the usual time for drug development, which is crucial for addressing morbidity and mortality that are caused by COVID-19 [37].…”

“…Interestingly, periodic mechanical motions influenced the experimental data [91]. Physiologically relevant in vitro platforms that mimic human diseases and can test the effects of drugs thereon have been highlighted by several models, such as a specific alveolar model [92], an alveolar barrier in respiratory dynamics [85], intravascular thrombosis in lung alveolus [93], small airway-on-a-chip [94], and human lung airway epithelial cells and pulmonary microvascular endothelial cells [36].…”

Breathing on Chip: Dynamic flow and stretch tune cellular composition and accelerate mucociliary maturation of airway epitheliumin vitro

“…However, spontaneous transmembrane migration of airway epithelial cells might also occur 27 . A possible strategy is the concurrent seeding of epithelial and endothelial cells onto either side of the membrane to prevent such behavior 28 . Unfortunately, this method precludes the study of either compartment in isolation, constrains the type of media that can be used during epithelial differentiation, and prevents full differentiation of the epithelial cells before endothelial cells undergo senescence or suffer from suboptimal co-culture medium.…”