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Dysregulation in mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells

Sofia Appelberg, Soham Gupta, Anoop T Ambikan, Flora Mikaeloff, Ákos Végvári, Sara Svensson Akusjärvi, Rui Benfeitas, Maike Sperk, Marie Ståhlberg, Shuba Krishnan, Kamal Singh, Josef M. Penninger, Ali Mirazimi, Ujjwal Neogi
doi: https://doi.org/10.1101/2020.04.30.070383
Sofia Appelberg
1Public Health Agency of Sweden, Solna, Sweden
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Soham Gupta
2Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
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Anoop T Ambikan
2Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
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Flora Mikaeloff
2Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
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Ákos Végvári
3Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Sara Svensson Akusjärvi
2Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
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Rui Benfeitas
4National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, S-10691 Stockholm, Sweden
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Maike Sperk
2Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
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Marie Ståhlberg
3Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Shuba Krishnan
2Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
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Kamal Singh
2Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
5Department of Molecular Microbiology and Immunology and the Bond Life Science Center, University of Missouri, Columbia, MO 65211, USA
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Josef M. Penninger
6Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-Gasse 3, 1030 Vienna, Austria
7Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, V6T 1Z3, British Columbia, Canada
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Ali Mirazimi
1Public Health Agency of Sweden, Solna, Sweden
2Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
8National Veterinary Institute, Uppsala, Sweden
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  • For correspondence: ali.mirazimi@folkhalsomyndigheten.se ujjwal.neogi@ki.se
Ujjwal Neogi
2Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
5Department of Molecular Microbiology and Immunology and the Bond Life Science Center, University of Missouri, Columbia, MO 65211, USA
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  • For correspondence: ali.mirazimi@folkhalsomyndigheten.se ujjwal.neogi@ki.se
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Abstract

How Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remain largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected HuH7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a significant reduction in activated S6K1 and 4E-BP1 at 72 hours post infection. Unlike other human respiratory viruses, we found a significant inhibition of HIF-1α through the entire time course of the infection, suggesting a crosstalk between the SARS-CoV-2 and the mTOR/HIF-1 signaling. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe COVID-19 patients.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://zenodo.org/record/3754719#.XqgnSy2B3OQ

  • https://github.com/neogilab/COVID19

  • https://www.ncbi.nlm.nih.gov/bioproject/PRJNA627100/

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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Posted May 01, 2020.
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Dysregulation in mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells
Sofia Appelberg, Soham Gupta, Anoop T Ambikan, Flora Mikaeloff, Ákos Végvári, Sara Svensson Akusjärvi, Rui Benfeitas, Maike Sperk, Marie Ståhlberg, Shuba Krishnan, Kamal Singh, Josef M. Penninger, Ali Mirazimi, Ujjwal Neogi
bioRxiv 2020.04.30.070383; doi: https://doi.org/10.1101/2020.04.30.070383
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Dysregulation in mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells
Sofia Appelberg, Soham Gupta, Anoop T Ambikan, Flora Mikaeloff, Ákos Végvári, Sara Svensson Akusjärvi, Rui Benfeitas, Maike Sperk, Marie Ståhlberg, Shuba Krishnan, Kamal Singh, Josef M. Penninger, Ali Mirazimi, Ujjwal Neogi
bioRxiv 2020.04.30.070383; doi: https://doi.org/10.1101/2020.04.30.070383

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