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

Abstract

In the current COVID-19 pandemic context, proposing and validating effective treatments represents a major challenge. However, the lack of biologically relevant pre-clinical experimental models of SARS-CoV-2 infection as a complement of classic cell lines represents a major barrier for scientific and medical progress. Here, we advantageously used human reconstituted airway epithelial models of nasal or bronchial origin to characterize viral infection kinetics, tissue-level remodeling of the cellular ultrastructure and transcriptional immune signatures induced by SARS-CoV-2. Our results underline the relevance of this model for the preclinical evaluation of antiviral candidates. Foremost, we provide evidence on the antiviral efficacy of remdesivir and the therapeutic potential of the remdesivir-diltiazem combination as a rapidly available option to respond to the current unmet medical need imposed by COVID-19.One Sentence SummaryNew insights on SARS-CoV-2 biology and drug combination therapies against COVID-19.

Broad-spectrum antiviral activity of naproxen: from Influenza A to SARS-CoV-2 Coronavirus

“…Conversely, significant reductions in intracellular SARS-CoV-2 viral titers were observed for the two treatment conditions in bronchial HAE (73 and 82% reduction vs mock-treated control, respectively). This reduction in viral titers correlated with naproxen inducing a protective effect of the bronchial epithelium Interestingly, we previously determined that the peak of viral replication was reached earlier in bronchial (48-72 hpi) than in nasal HAE, in which a progressive increase in infectious viral titers was observed until at least 96 hpi 23 . Using this model, this differential antiviral effect between airway sites was observed for naproxen in this work and for remdesivir in a recent report that indicates an antiviral effect mainly observed in the lower respiratory tract of non-Human primates 23 .…”

“…This reduction in viral titers correlated with naproxen inducing a protective effect of the bronchial epithelium Interestingly, we previously determined that the peak of viral replication was reached earlier in bronchial (48-72 hpi) than in nasal HAE, in which a progressive increase in infectious viral titers was observed until at least 96 hpi 23 . Using this model, this differential antiviral effect between airway sites was observed for naproxen in this work and for remdesivir in a recent report that indicates an antiviral effect mainly observed in the lower respiratory tract of non-Human primates 23 . It is interesting to note that naproxen is found very protective against viral-induced damages at 48 h post-infection in the reconstituted bronchial epithelium ( Figure 2C and Figure 4 in 23 ).…”

“…We further evaluated the antiviral effect of naproxen using a more biologically relevant experimental model, notably the nasal and bronchial MucilAir TM reconstituted human airway epithelia (HAE) 23 .…”

“…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 in the early stages of infection and constitute robust surrogates to study airway disease mechanisms and for drug discovery 23 . Post-infection treatment of nasal HAE with 90 or 300 µM naproxen did not show an antiviral effect at 48 hpi compared to the mock-treated control (Fig.…”

Cell-intrinsic differences between human airway epithelial cells from children and adults

“…Nevertheless, cell culture conditions alter basal cell gene expression more significantly than inter-patient variability (Butler et al, 2016), so comparing ACE2 protein expression across basal cell culture systems might be of interest. Basal cells can also be differentiated towards mucosecretory and ciliated lineages in scalable air-liquid interface or organoid (Sachs et al, 2019) cultures that contain the cellular lineages thought to be targeted by SARS-CoV-2 in patients, suggesting these for use in viral infection studies (Jonsdottir and Dijkman, 2016;Pizzorno et al, 2020).…”