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Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells.
Emerg Microbes Infect. 2020 Dec; 9(1):1748-1760.EM

Abstract

How severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remains 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 dose-dependent activation of Akt, mTOR, S6K1 and 4E-BP1 at 24 hours post infection (hpi). However, we found a significant inhibition of HIF-1α through 24hpi and 48hpi of the infection, suggesting a crosstalk between the SARS-CoV-2 and the Akt/mTOR/HIF-1 signaling pathways. Inhibition of the mTOR signaling pathway using Akt inhibitor MK-2206 showed a significant reduction in virus production. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe coronavirus disease 2019 (COVID-19) patients.

Authors+Show Affiliations

Public Health Agency of Sweden, Solna, Sweden.Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University Stockholm, Sweden.Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden. Department of Veterinary Pathobiology and the Bond Life Science Center, University of Missouri, Columbia, MO, USA.Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, Canada.Public Health Agency of Sweden, Solna, Sweden. Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden. National Veterinary Institute, Uppsala, Sweden.Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden. Department of Veterinary Pathobiology and the Bond Life Science Center, University of Missouri, Columbia, MO, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32691695

Citation

Appelberg, Sofia, et al. "Dysregulation in Akt/mTOR/HIF-1 Signaling Identified By Proteo-transcriptomics of SARS-CoV-2 Infected Cells." Emerging Microbes & Infections, vol. 9, no. 1, 2020, pp. 1748-1760.
Appelberg S, Gupta S, Svensson Akusjärvi S, et al. Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells. Emerg Microbes Infect. 2020;9(1):1748-1760.
Appelberg, S., Gupta, S., Svensson Akusjärvi, S., Ambikan, A. T., Mikaeloff, F., Saccon, E., Végvári, Á., Benfeitas, R., Sperk, M., Ståhlberg, M., Krishnan, S., Singh, K., Penninger, J. M., Mirazimi, A., & Neogi, U. (2020). Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells. Emerging Microbes & Infections, 9(1), 1748-1760. https://doi.org/10.1080/22221751.2020.1799723
Appelberg S, et al. Dysregulation in Akt/mTOR/HIF-1 Signaling Identified By Proteo-transcriptomics of SARS-CoV-2 Infected Cells. Emerg Microbes Infect. 2020;9(1):1748-1760. PubMed PMID: 32691695.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells. AU - Appelberg,Sofia, AU - Gupta,Soham, AU - Svensson Akusjärvi,Sara, AU - Ambikan,Anoop T, AU - Mikaeloff,Flora, AU - Saccon,Elisa, AU - Végvári,Ákos, AU - Benfeitas,Rui, AU - Sperk,Maike, AU - Ståhlberg,Marie, AU - Krishnan,Shuba, AU - Singh,Kamal, AU - Penninger,Josef M, AU - Mirazimi,Ali, AU - Neogi,Ujjwal, PY - 2020/7/22/pubmed PY - 2020/8/12/medline PY - 2020/7/22/entrez KW - Akt/mTOR/HIF-1 KW - MK-2206 KW - SARS-CoV-2 KW - proteomics KW - transcriptomics SP - 1748 EP - 1760 JF - Emerging microbes & infections JO - Emerg Microbes Infect VL - 9 IS - 1 N2 - How severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remains 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 dose-dependent activation of Akt, mTOR, S6K1 and 4E-BP1 at 24 hours post infection (hpi). However, we found a significant inhibition of HIF-1α through 24hpi and 48hpi of the infection, suggesting a crosstalk between the SARS-CoV-2 and the Akt/mTOR/HIF-1 signaling pathways. Inhibition of the mTOR signaling pathway using Akt inhibitor MK-2206 showed a significant reduction in virus production. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe coronavirus disease 2019 (COVID-19) patients. SN - 2222-1751 UR - https://www.unboundmedicine.com/medline/citation/32691695/Dysregulation_in_Akt/mTOR/HIF_1_signaling_identified_by_proteo_transcriptomics_of_SARS_CoV_2_infected_cells_ L2 - https://www.tandfonline.com/doi/full/10.1080/22221751.2020.1799723 DB - PRIME DP - Unbound Medicine ER -