Transcriptomics-inferred dynamics of SARS-CoV-2 interactions with host epithelial cells

Author:

Adam Lukas1ORCID,Stanifer Megan23ORCID,Springer Fabian1ORCID,Mathony Jan4567ORCID,Brune Maik8,Di Ponzio Chiara19,Eils Roland19,Boulant Steeve2310ORCID,Niopek Dominik457ORCID,Kallenberger Stefan M.11112ORCID

Affiliation:

1. Health Data Science Unit, University Hospital Heidelberg and Center for Quantitative Analysis of Molecular and Cellular Biosystems (BioQuant), University of Heidelberg, Heidelberg 69120, Germany.

2. Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg 69120, Germany.

3. Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32603, USA.

4. Department of Biology, Technical University of Darmstadt, Darmstadt 64287, Germany.

5. Center for Synthetic Biology, Technical University of Darmstadt, Darmstadt 64287, Germany.

6. BZH Graduate School, Heidelberg University, Heidelberg 69120, Germany.

7. Institute of Pharmacy and Molecular Biotechnology (IPMB), Faculty of Engineering Sciences, Heidelberg University, Heidelberg 69120, Germany.

8. Clinic of Endocrinology, Diabetology, Metabolism, and Clinical Chemistry, Central Laboratory, Heidelberg University Hospital, Heidelberg 69120, Germany.

9. Digital Health Center, Berlin Institute of Health (BIH) and Charité, Berlin 10178, Germany.

10. Research Group “Cellular polarity and viral infection” (F140), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

11. Division of Applied Bioinformatics (G200), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

12. National Center for Tumor Diseases, Department of Medical Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany.

Abstract

Virus-host interactions can reveal potentially effective and selective therapeutic targets for treating infection. Here, we performed an integrated analysis of the dynamics of virus replication and the host cell transcriptional response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using human Caco-2 colon cancer cells as a model. Time-resolved RNA sequencing revealed that, upon infection, cells immediately transcriptionally activated genes associated with inflammatory pathways that mediate the antiviral response, which was followed by an increase in the expression of genes involved in ribosome and mitochondria function, thus suggesting rapid alterations in protein production and cellular energy supply. At later stages, between 24 and 48 hours after infection, the expression of genes involved in metabolic processes—in particular, those related to xenobiotic metabolism—was decreased. Mathematical modeling incorporating SARS-CoV-2 replication suggested that SARS-CoV-2 proteins inhibited the host antiviral response and that virus transcripts exceeded the translation capacity of the host cells. Targeting kinase-dependent pathways that exhibited increases in transcription in host cells was as effective as a virus-targeted inhibitor at repressing viral replication. Our findings in this model system delineate a sequence of SARS-CoV-2 virus-host interactions that may facilitate the identification of druggable host pathways to suppress infection.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Cell Biology,Molecular Biology,Biochemistry

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