Yazdan Yazdanpanah, Manuel Rosa-Calatrava, Andrés Pizzorno, Julia Dubois, François Xavier Lescure, Pauline Brun, Blandine Padey, Victoria Dulière, Aurélien Traversier, Alexandre Gaymard, Sophie Trouillet-Assant, Bruno Lina, Olivier Terrier, Samuel Constant, Thomas Julien, Julien Poissy, Julien Fouret, Elisabeth Errazuriz-Cerda, Université de Lille, CNRS, Virology and human respiratory Pathologies - Virology and human respiratory Pathologies [VirPath], Université Claude Bernard Lyon 1 [UCBL], Infection, Anti-microbiens, Modélisation, Evolution [IAME (UMR_S_1137 / U1137)], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Faculté de Médecine Henri Warembourg - Université de Lille, Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control (Virpath), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, ANR-20-COVI-0052,CorPopImm,Évaluer l'immunité contre SARS-CoV-2 à l'échelle de la population grâce aux tests sérologiques(2020), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, and Université Lille 2 - Faculté de Médecine
Summary In the current COVID-19 pandemic context, proposing and validating effective treatments represents a major challenge. However, the scarcity of biologically relevant pre-clinical models of SARS-CoV-2 infection imposes a significant barrier for scientific and medical progress, including the rapid transition of potentially effective treatments to the clinical setting. We use reconstituted human airway epithelia to isolate and then characterize the viral infection kinetics, tissue-level remodeling of the cellular ultrastructure, and transcriptional early immune signatures induced by SARS-CoV-2 in a physiologically relevant model. Our results emphasize distinctive transcriptional immune signatures between nasal and bronchial HAE, both in terms of kinetics and intensity, hence suggesting putative intrinsic differences in the early response to SARS-CoV-2 infection. Most important, we provide evidence in human-derived tissues on the antiviral efficacy of remdesivir monotherapy and explore the potential of the remdesivir-diltiazem combination as an option worthy of further investigation to respond to the still-unmet COVID-19 medical need., Graphical Abstract, Highlights We use reconstituted human airway epithelia to characterize SARS-CoV-2 infection kinetics SARS-CoV-2 induces characteristic remodeling of the respiratory epithelium cellular ultrastructure SARS-CoV-2 induces differential early immune responses in nasal and bronchial HAE We evaluate the antiviral activity of remdesivir and remdesivir-diltiazem in both Vero E6 and HAE models, Pizzorno et al. report the characterization of SARS-CoV-2 infection, tissue-level remodeling of cellular ultrastructure, and transcriptional immune signatures using a model of reconstituted human airway epithelia. This model was advantageously used to evaluate the antiviral activity of remdesivir or a combination of remdesivir-diltiazem against SARS-CoV-2.