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Authors: Wyler Emanuel, Mösbauer Kirstin, Franke Vedran, Diag Asija, Gottula Lina Theresa, Arsie Roberto, Klironomos Filippos, Koppstein David, Ayoub Salah, Buccitelli Christopher, Richter Anja, Legnini Ivano, Ivanov Andranik, Mari Tommaso, Del Giudice Simone, Papies Jan Patrick, Müller Marcel Alexander, Niemeyer Daniela, Selbach Matthias, Akalin Altuna, Rajewsky Nikolaus, Drosten Christian, Landthaler Markus.

Link to paper: https://www.biorxiv.org/content/10.1101/2020.05.05.079194v1

Journal/ Pre-Print: BioRxiv

Tags: Bioinformatics, Cell Biology, Drug discovery/Drug repurpose, Immunology/Immunity, Inflammation, Therapeutics, Virology

Research Highlights

1. Inhibition of HSP90 by 17-AAG at high nanomolar concentrations can reduce SARS-CoV2 replication and TNF and IL1B mRNA levels in the Calu-3 cell line.

2. scRNAseq of infected cell lines demonstrates that only a subset of infected cells upregulate interferon β. From the data shown the correlation of this subset to time point (hpi) and/or biological replicate is unclear.

3. Both SARS-CoV & SARS-CoV2 lead to significant upregulation of microRNA miR-155 in Calu-3 cells.

Summary

The authors sequenced bulk mRNA, viral RNA, microRNA, and single cell mRNA from 3 cell lines infected with SARS-CoV or SARS-CoV2. SARS-CoV2 replication was high in the Calu-3 (lung epithelial) and Caco-2 (gut epithelial) cell lines and low in the H1299 (lung epithelial) cell line, possibly linked to ACE2 expression levels. Expression of interferon-stimulated genes, microRNAs, ARRDC3, some NF-κB targets, and HSP90 (an indicator of ER stress) was compared between the 3 cell lines, and between SARS-CoV2 vs. SARS-CoV infection. Because HSP90 inhibition decreased viral replication in vitro and inhibitors are already in clinical development, this could prove an interesting target for SARS-CoV2 inhibition.

Impact for SARS-CoV2/COVID19 research efforts

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

Treat of SARS-CoV2/COVID19 positive individuals

Study Type

· In vitro study

Strengths and limitations of the paper

Novelty: This study confirms that HSP90 inhibition reduces in vitro SARS-CoV2 growth.

Standing in the field: > There is evidence that HSP90 inhibition can also decrease viral replication in influenza models. Inhibition of SARS-CoV2 replication was recently proposed based on a computational analysis.

> A role for miRNA-155 in viral pathogenesis has been reported before. A mouse model of influenza demonstrated reduced ARDS upon miRNA-155 inhibition, indicating it may be a possible therapeutic target in Covid-19 too.

Appropriate statistics: Partially. For many comparisons between conditions no statistical testing is applied at all. Also, it is unclear if the GSEA results displayed are unbiased or the result of “cherry picking”.

Viral model used: SARS-CoV-2 (Patient isolate 985, BetaCoV/Munich/BavPat1/2020 |EPI_ISL_406862) & SARS-CoV (Frankfurt strain)

Translatability: Possible evidence that repurposing HSP90 inhibitors could be valuable, but quite far from bedside because it is an in vitro study.

Main limitations: > The biological replicates for scRNAseq analysis show wildly different viral replication rates but the authors don’t comment on this.

> Some plots (e.g. scRNAseq clustering) are difficult to read, and figure legends are incomplete.

> Conclusions are drawn without appropriate statistical testing to back them up.

> The RNA velocity data don’t show a clear trajectory. It is unclear why the pseudotime was shown for bins of 50 cells instead of for single cells.