Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model

Abstract

Respiratory viral infections cause mild to severe diseases, such as common cold, bronchiolitis and pneumonia and are associated with substantial burden for society. To test new molecules for shortening, alleviating the diseases or to develop new therapies, relevant human in vitro models are mandatory. MucilAir™, a human standardized air-liquid interface 3D airway epithelial culture holds in vitro specific mechanisms to counter invaders comparable to the in vivo situation, such as mucus production, mucociliary clearance, and secretion of defensive molecules. The objective of this study was to test the relevance of such a model for the discovery and validation of antiviral drugs. Fully differentiated 3D nasal epithelium cultures were inoculated with picornaviruses, a coronavirus and influenza A viruses in the absence or in the presence of reference antiviral drugs. Results showed that, rupintrivir efficiently inhibits the replication of respiratory picornaviruses in a dose dependent manner and prevents the impairment of the mucociliary clearance. Similarly, oseltamivir reduced the replication of influenza A viruses in a dose dependent manner and prevented the impairment of the epithelial barrier function and cytotoxicity until 4 days of infection. In addition we found that Rhinovirus B14, C15 and influenza A(H1N1) induce significant increase of β Defensins 2 and Cathelicidin release with different time course. These results reveal that a large panel of epithelial functions is modified upon viral infection and validate MucilAir™ as a pertinent tool for pre-clinical antiviral drug testing.

Characterization and treatment of SARS-CoV-2 in nasal and bronchial human airway epithelia

“…We and others have previously 65 reported the advantage of using more physiological models such as in-house or commercially available reconstituted human airway epithelia (HAE) to isolate, culture and study a wide range of respiratory viruses (8,9). Developed from biopsies of nasal or bronchial cells differentiated in the air/liquid interphase, these models reproduce with high fidelity most of the main structural, functional and innate immune features of the human respiratory epithelium that play a central role 70 in the early stages of infection and constitute robust surrogates to study airway disease mechanisms and for drug discovery (10).…”

Efficacy of a seawater solution enriched with copper, hyaluronic acid and eucalyptus against nasal pathogens

“…The activity of the main epithelial ionic channels, such as CFTR, EnaC, Na/K ATPase, is preserved and the epithelia is shown to respond in a regulated and vectorial manner to the pro-inflammatory stimulus, TNF-a (27) . A large panel of Most importantly, MucilAir™ replicates the main function of the airway epithelial cells, the mucociliary clearance driven by synchronized cilia-beating, and has been successfully used for acute, long-term and chronic in vitro studies (16,17,28,29) . Given that MucilAir™ is functionally robust and successfully mimics human nasal epithelium, it is important to conduct a clinical trial with SSPCF in order to demonstrate the safety and efficacy of it in in vivo settings.…”

Elucidating the Interaction of CF Airway Epithelial Cells and Rhinovirus: Using the Host-Pathogen Relationship to Identify Future Therapeutic Strategies

“…Finally, monolayer cell cultures which have previously been found to be more susceptible for RV infection (Bochkov et al, 2010 ) represent an oversimplified model for the multicellular interactions of epithelial (ciliated cells, goblet cells) and immune cells (dendritic cells, neutrophils). Indeed, functional validation utilizing human in vitro 3D airway models (Boda et al, 2018 ) will be needed to further elucidate to host-pathogen interactions. The emergence of single cell transcriptomics could be used to compliment 3D airway models and accelerate progress in this new era of scientific research.…”