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Authors: Daniel Blanco-Melo et al

Link to paper: https://www.biorxiv.org/content/10.1101/2020.03.24.004655v1

Journal/ Pre-Print: bioRxiv

Key Words: Transcriptomic; Host transcriptional response; Influenza A; Respiratory syncytial virus (RSV), Bulk RNA-s

Research Highlights

1. Mild host transcriptional response to SARS-CoV-2 in human cells and ferrets when compared to response elicited by Influenza A and RSV

2. No robust induction of Type I and III interferons following SARS-CoV-2 infection

3. Host transcriptional profile to SARS-CoV-2 different from Influenza A and RSV in vivo but resembles RSV in vitro

Summary

Blanco-Melo et al. demonstrate in this preprint a transcriptome profile of lung alveolar epithelial cells in response to SARS-CoV2, Influenza A virus & RSV infections in vitro and the transcriptome profile of nasal washes obtained from SARS-CoV2 infected ferrets. Transcriptome analysis shows 120 differently expressed genes in response to SARS-CoV2 and a different gene expression pattern compared to IAV and RSV infections. Type I & III interferon expression was not induced upon SARS-CoV2 infection but two uniquely upregulated molecules (EDN1 & TNFSF15) for SARS-CoV2, could be detected.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19:

RNA-seq data of human lung epithelial cells infected with SARS-CoV-2 provides the list of immunity genes responding to the virus infection.

Understand the virology and/or cell biology of SARS-CoV2/COVID19:

SARS-CoV-2 can enter A549 cells, which express extremely low level of ACE2 and TMPRSS2 that are required for virus entry in the cell. Data supporting another potential entry route through BSG for the virus.

Helps to compare response of lung epithelium in context of other respiratory virus which could be beneficial in re-purposing existing treatments from other respiratory viruses

Develop diagnostic tools for SARS-CoV2/COVID19: More data required but gene expression pattern specific to SARS-Cov-2 infection could provide potential biomarkers, such as the secreted peptides EDN1 & TNFSF15.

Study Type

· Bioinformatics study – Transcriptome analysis

· In vitro study: A549 and NHBE cells

· In vivo study (e.g. mouse, NHP): Ferret model.

Strengths and limitations of the paper

Novelty: Full transcriptional profile of lung epithelial cell line, primary cells & in vivo cells after SARS-CoV2 infection: SARS-CoV-2 elicits a mild host transcriptional response, exemplified by the lack of induction of Type I and III interferons. Possibility of induction of two novel immune genes EDN1 & TNFSF15 specific to SARS-CoV-2, which could be use as biomarkers.

Standing in the field: This is one of the transcriptomic analyses of the host response to SARS-CoV-2 infection. Several other single cell RNASEq studies of patient PBMCs or lung bronchoalveolar immune cells are in the preprints as well. The results shown for Influenza A and RSV seem to agree with what has been published before for these two viruses.

Appropriate statistics: Unclear, the number of biological replicates for the RNA-seq is not available.

Viral model used: SARS-CoV2; Influenza A; Respiratory syncytial virus in in vitro and in vivo systems

Translatability: None.

Main limitations:

- RNA-seq analysis not performed in presence of spike-ins for data normalization. Therefore, the analysis might not be entirely correct. Also, a single time-point has been used, which might not represent the whole picture of the host transcriptional response to SARS-CoV-2 infection.

- For the cell line infection & primary cell infection, an alveolar epithelium (lower respiratory tract) model was used. For analysis of in vivo infection nasal washes (upper respiratory tract) were performed. These differences in localization and cellular composition might pose a challenge in comparing the transcriptional profiles and it would have been better if epithelial cell lines and in vivo model would have been consistent.