SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery
drug discovery/repurposing virology
Authors:A. Mulay et al
Link to paper: https://doi.org/10.1101/2020.06.29.174623
Tags: Drug discovery (testing platform), Modelling (new cellular culture models), Virology
Confirmation of SARS-CoV-2 infection, replication and treatment within air liquid interface and 3D alveolar organoids, which makes it a suitable tool for further studies.
SARS-CoV-2 infection elicits a robust innate immune and interferon gene signature
Remdesivir pre-treatment significantly dampens viral replication in organoid cultures
Mulay et al. established air-liquid interface (ALI) cultures and 3D alveolar epithelial organoid cultures to study SARS-CoV-2 infection and establish a platform for therapeutic target exploration. Infection of proximal airway ALI cultures was heterogenous and the virus targeted mainly ciliated cells. Using the 3D model, Alveolar Type 2 cells were identified as susceptible to SARS-CoV-2, whereby the infection triggered cell-autonomous and non-cell-autonomous apoptosis. Virus replication and gene transcription in the model was confirmed and an induction of an innate immune/interferon signature was observed. In this system, remdesivir was better able to reduce SARS-CoV-2 viral replication than hydroxychloroquine.
Impact for SARS-CoV2/COVID19 research efforts
Develop diagnostic tools for SARS-CoV2/COVID19
Treat of SARS-CoV2/COVID19 positive individuals: the lung organoid system established in this study could be used to identify novel drug targets for COVID-19.
In vitro study
Strengths and limitations of the paper
Novelty: Establishment of a primary in vitro system of adult human alveoli to model COVID-19, where drug screens can be performed.
Standing in the field: Ciliated cells and AT2 cells as SARS-CoV-2 targets also reported in other studies. SARS-CoV-2 has previously been shown to infect bronchial organoids (Suzuki et al, BioRxiv, 2020) and 2D airway epithelium (Lamers et al, Science, 2020). The interferon signature upon infection has also been described for intestinal organoids (Lamers et al, Science, 2020) and fits with current literature. Additionally, remdesivir has been shown to diminish SARS-CoV-2 infectivity in iPSC-derived intestinal organoids (Kruger et al, BioRxiv, 2020).
Appropriate statistics: Yes
Viral model used: SARS-CoV-2, isolate USA- WA1/2020
Translatability: Novel platform for infection and drug target studies
Relatively long workflow to set up the model system cultures (up to 5-6 weeks).
Culture systems rely on cells derived from different donors which might result in differences in disease outcomes.
How do drug concentrations/drug half-life used in this study relate to the patient setting?
Since drugs were added before infection, would these results still hold true with drug treatment after infection? This would be crucial since in the patient setting, remdesivir is used to treat patients and not as a preventative measure.
A further discussion of the results and how they fit with the literature would be helpful.
Figure 3 (a-d): Axis labelling unclear, further information needed