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Bulk and single-cell gene expression profiling of SARS-CoV-2 infected human cell lines identifies molecular targets for therapeutic intervention

View ORCID ProfileWyler Emanuel, Mösbauer Kirstin, View ORCID ProfileFranke Vedran, Diag Asija, Gottula Lina Theresa, Arsie Roberto, Klironomos Filippos, View ORCID ProfileKoppstein David, View ORCID ProfileAyoub Salah, Buccitelli Christopher, Richter Anja, View ORCID ProfileLegnini Ivano, Ivanov Andranik, Mari Tommaso, Del Giudice Simone, Papies Jan Patrick, Müller Marcel Alexander, Niemeyer Daniela, View ORCID ProfileSelbach Matthias, View ORCID ProfileAkalin Altuna, View ORCID ProfileRajewsky Nikolaus, View ORCID ProfileDrosten Christian, View ORCID ProfileLandthaler Markus
doi: https://doi.org/10.1101/2020.05.05.079194
Wyler Emanuel
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
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  • ORCID record for Wyler Emanuel
  • For correspondence: markus.landthaler@mdc-berlin.de christian.drosten@charite.de emanuel.wyler@mdc-berlin.de
Mösbauer Kirstin
2Institute of Virology, Charité-Universitätsmedizin Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany
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Franke Vedran
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
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Diag Asija
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
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Gottula Lina Theresa
2Institute of Virology, Charité-Universitätsmedizin Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany
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Arsie Roberto
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
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Klironomos Filippos
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
4Department of Pediatrics, Charité – University Hospital Berlin, 13353 Berlin, Germany
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Koppstein David
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
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Ayoub Salah
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
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Buccitelli Christopher
3Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Strasse 10, 1312, Berlin, Germany
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Richter Anja
2Institute of Virology, Charité-Universitätsmedizin Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany
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Legnini Ivano
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
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Ivanov Andranik
5Core Unit Bioinformatics, Berlin Institute of Health, Charité – University Hospital Berlin, 10117 Berlin, Germany
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Mari Tommaso
3Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Strasse 10, 1312, Berlin, Germany
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Del Giudice Simone
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
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Papies Jan Patrick
2Institute of Virology, Charité-Universitätsmedizin Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany
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Müller Marcel Alexander
2Institute of Virology, Charité-Universitätsmedizin Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany
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Niemeyer Daniela
2Institute of Virology, Charité-Universitätsmedizin Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany
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Selbach Matthias
3Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Strasse 10, 1312, Berlin, Germany
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Akalin Altuna
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
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Rajewsky Nikolaus
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
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Drosten Christian
2Institute of Virology, Charité-Universitätsmedizin Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany
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  • For correspondence: markus.landthaler@mdc-berlin.de christian.drosten@charite.de emanuel.wyler@mdc-berlin.de
Landthaler Markus
1Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str 28, 10115 Berlin, Germany
6IRI Life Sciences, Institut für Biologie, Humboldt Universität zu Berlin, Philippstraße 13, 10115, Berlin, Germany
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  • For correspondence: markus.landthaler@mdc-berlin.de christian.drosten@charite.de emanuel.wyler@mdc-berlin.de
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Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing global health threat with more than two million infected people since its emergence in late 2019. Detailed knowledge of the molecular biology of the infection is indispensable for understanding of the viral replication, host responses, and disease progression. We provide gene expression profiles of SARS-CoV and SARS-CoV-2 infections in three human cell lines (H1299, Caco-2 and Calu-3 cells), using bulk and single-cell transcriptomics. Small RNA profiling showed strong expression of the immunity and inflammation-associated microRNA miRNA-155 upon infection with both viruses. SARS-CoV-2 elicited approximately two-fold higher stimulation of the interferon response compared to SARS-CoV in the permissive human epithelial cell line Calu-3, and induction of cytokines such as CXCL10 or IL6. Single cell RNA sequencing data showed that canonical interferon stimulated genes such as IFIT2 or OAS2 were broadly induced, whereas interferon beta (IFNB1) and lambda (IFNL1-4) were expressed only in a subset of infected cells. In addition, temporal resolution of transcriptional responses suggested interferon regulatory factors (IRFs) activities precede that of nuclear factor-κB (NF-κB). Lastly, we identified heat shock protein 90 (HSP90) as a protein relevant for the infection. Inhibition of the HSP90 charperone activity by Tanespimycin/17-N-allylamino-17-demethoxygeldanamycin (17-AAG) resulted in a reduction of viral replication, and of TNF and IL1B mRNA levels. In summary, our study established in vitro cell culture models to study SARS-CoV-2 infection and identified HSP90 protein as potential drug target for therapeutic intervention of SARS-CoV-2 infection.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE148729

  • https://www.mdc-berlin.de/singlecell-SARSCoV2

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Bulk and single-cell gene expression profiling of SARS-CoV-2 infected human cell lines identifies molecular targets for therapeutic intervention
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
bioRxiv 2020.05.05.079194; doi: https://doi.org/10.1101/2020.05.05.079194
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Bulk and single-cell gene expression profiling of SARS-CoV-2 infected human cell lines identifies molecular targets for therapeutic intervention
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
bioRxiv 2020.05.05.079194; doi: https://doi.org/10.1101/2020.05.05.079194

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