Characterization and Treatment of SARS-CoV-2 in Nasal and Bronchial Human Airway Epithelia

Pizzorno, Andrés; Padey, Blandine; Julien, Thomas; Trouillet‐Assant, Sophie; Traversier, Aurélien; Errazuriz-Cerda, Elisabeth; Fouret, Julien; Dubois, Julia; Gaymard, Alexandre; Lescure, François Xavier; Dulière, Victoria; Brun, Pauline; Constant, Samuel; Poissy, Julien; Lina, Bruno; Yazdanpanah, Yazdan; Terrier, B.; Rosa‐Calatrava, Manuel

doi:10.1016/j.xcrm.2020.100059

Cited by 214 publications

(262 citation statements)

References 30 publications

Supporting

Mentioning

225

Contrasting

Unclassified

Order By: Relevance

“…. As shown previously (Pizzorno et al, 2020), these primary cells were highly permissive to SARS-CoV-2 replication.…”

supporting

confidence: 82%

SARS-CoV-2 replication triggers an MDA-5-dependent interferon production which is unable to efficiently control replication

Rebendenne

Luiza

Tauziet

et al. 2020

Preprint

View full text Add to dashboard Cite

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third highly pathogenic coronavirus to spill over to humans in less than 20 years, after SARS-CoV-1 in 2002-2003 and Middle East respiratory syndrome (MERS)-CoV in 2012. SARS-CoV-2 is the etiologic agent of coronavirus disease 19 (COVID-19), which ranges from mild respiratory symptoms to severe lung injury and death in the most severe cases. The COVID-19 pandemic is currently a major health issue worldwide. Immune dysregulation characterized by altered innate cytokine responses is thought to contribute to the pathology of COVID-19 patients, which is a testimony of the fundamental role of the innate immune response against SARS-CoV-2. Here, we further characterized the host cell antiviral response against SARS-CoV-2 by using primary human airway epithelia and immortalized model cell lines. We mainly focused on the type I and III interferon (IFN) responses, which lead to the establishment of an antiviral state through the expression of IFN-stimulated genes (ISGs). Our results demonstrate that both primary airway epithelial cells and model cell lines elicit a robust immune response characterized by a strong induction of type I and III IFN through the detection of viral pathogen molecular patterns (PAMPs) by melanoma differentiation associated gene (MDA)-5. However, despite the high levels of type I and III IFNs produced in response to SARS-CoV-2 infection, the IFN response was unable to control viral replication, whereas IFN pre-treatment strongly inhibited viral replication and de novo production of infectious virions. Taken together, these results highlight the complex and ambiguous interplay between viral replication and the timing of IFN responses.

show abstract

“…. As shown previously (Pizzorno et al, 2020), these primary cells were highly permissive to SARS-CoV-2 replication.…”

supporting

confidence: 82%

SARS-CoV-2 replication triggers an MDA-5-dependent interferon production which is unable to efficiently control replication

Rebendenne

Luiza

Tauziet

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Although prior reports had suggested SARS-CoV-2 to cause a decreased TEER (Pizzorno et al, 2020), in this study SARS-CoV-2 did not modify tissue integrity, Figure 5.…”

Section: Discussioncontrasting

confidence: 61%

Evaluation of nafamostat mesylate safety and inhibition of SARS-CoV-2 replication using a 3-dimensional human airway epithelia model

Kirkpatrick

Millard

2020

Preprint

View full text Add to dashboard Cite

In the current COVID-19 pandemic context, Ensysce and its subsidiary Covistat have been working to repurpose nafamostat mesylate as an effective oral and inhalation treatment against SARS-CoV-2 infection. Prior reports used cell lines to demonstrate the antiviral potential of nafamostat against coronaviral infections and determined its mechanism of action through inhibition of transmembrane protease serine 2 (TMPRSS2). We selected a biologically relevant pre-clinical experimental model of SARS-CoV-2 lung infection using a 3D human reconstituted airway epithelial model of nasal origin to characterize the effects of nafamostat on tissue-level cellular ultrastructure and viral infection kinetics. Our results confirm the not only the relevance of this model for the preclinical evaluation of safety and efficacy of antiviral candidates, but also the highly potent nature of nafamostat SARS-CoV-2 antiviral activity. The studies described herein provided evidence demonstrating the therapeutic potential of nafamostat against COVID-19, as well as its safety upon exposure to lung airway cellular.One Sentence SummaryUsing a human airway model, study demonstrates the powerful inhibitory effect of nafamostat on SARS-CoV-2 genome copy detection when applied apically.

show abstract

“…We used the summary statistics reported in the summary for compassionate use of remdesivir filed by Gilead to the European Medicines Evaluation Agency (EMEA) 16 to derive the mean concentration of the active metabolite in peripheral blood mononuclear cell, mean serum concentration (C mean ), using the area under the curve (AUC) after a loading dose of 200 mg and after repeated doses of 100 mg q.d., and we assumed that the EC 50 for the metabolite was equal to the EC 50 of the parent. 17…”

Section: Model Including An Innate Immune Responsementioning

confidence: 99%

Timing of Antiviral Treatment Initiation is Critical to Reduce SARS‐CoV‐2 Viral Load

Gonçalves

Bertrand

et al. 2020

CPT Pharmacom & Syst Pharma

Self Cite

204

271

View full text Add to dashboard Cite

We modeled the viral dynamics of 13 untreated patients infected with severe acute respiratory syndrome‐coronavirus 2 to infer viral growth parameters and predict the effects of antiviral treatments. In order to reduce peak viral load by more than two logs, drug efficacy needs to be > 90% if treatment is administered after symptom onset; an efficacy of 60% could be sufficient if treatment is initiated before symptom onset. Given their pharmacokinetic/pharmacodynamic properties, current investigated drugs may be in a range of 6–87% efficacy. They may help control virus if administered very early, but may not have a major effect in severely ill patients.

show abstract

Characterization and Treatment of SARS-CoV-2 in Nasal and Bronchial Human Airway Epithelia

Cited by 214 publications

References 30 publications

SARS-CoV-2 replication triggers an MDA-5-dependent interferon production which is unable to efficiently control replication

SARS-CoV-2 replication triggers an MDA-5-dependent interferon production which is unable to efficiently control replication

Evaluation of nafamostat mesylate safety and inhibition of SARS-CoV-2 replication using a 3-dimensional human airway epithelia model

Timing of Antiviral Treatment Initiation is Critical to Reduce SARS‐CoV‐2 Viral Load

Contact Info

Product

Resources

About