SARS-CoV-2-infected human airway epithelial cell cultures uniquely lack interferon and immediate early gene responses caused by other coronaviruses

Ying Wang; Melissa Thaler; Clarisse Salgado-Benvindo; Nathan Ly; Anouk A Leijs; Dennis K Ninaber; Philip M Hansbro; Fia Boedijono; Martijn J van Hemert; Pieter S Hiemstra; Anne M van der Does; Alen Faiz

doi:10.1002/cti2.1503

SARS-CoV-2-infected human airway epithelial cell cultures uniquely lack interferon and immediate early gene responses caused by other coronaviruses

Clin Transl Immunology. 2024 Apr 15;13(4):e1503. doi: 10.1002/cti2.1503. eCollection 2024.

Affiliations

¹ PulmoScience Lab, Department of Pulmonology Leiden University Medical Center Leiden The Netherlands.
² Department of Medical Microbiology Leiden University Medical Center Leiden The Netherlands.
³ Respiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences University of Technology Sydney Sydney NSW Australia.
⁴ Centre for Inflammation Centenary Institute and University of Technology Sydney, Faculty of Science Sydney NSW Australia.

Abstract

Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of a class of highly pathogenic coronaviruses. The large family of coronaviruses, however, also includes members that cause only mild symptoms, like human coronavirus-229E (HCoV-229E) or OC43 (HCoV-OC43). Unravelling how molecular (and cellular) pathophysiology differs between highly and low pathogenic coronaviruses is important for the development of therapeutic strategies.

Methods: Here, we analysed the transcriptome of primary human bronchial epithelial cells (PBEC), differentiated at the air-liquid interface (ALI) after infection with SARS-CoV-2, SARS-CoV, Middle East Respiratory Syndrome (MERS)-CoV and HCoV-229E using bulk RNA sequencing.

Results: ALI-PBEC were efficiently infected by all viruses, and SARS-CoV, MERS-CoV and HCoV-229E infection resulted in a largely similar transcriptional response. The response to SARS-CoV-2 infection differed markedly as it uniquely lacked the increase in expression of immediate early genes, including FOS, FOSB and NR4A1 that was observed with all other coronaviruses. This finding was further confirmed in publicly available experimental and clinical datasets. Interfering with NR4A1 signalling in Calu-3 lung epithelial cells resulted in a 100-fold reduction in extracellular RNA copies of SARS-CoV-2 and MERS-CoV, suggesting an involvement in virus replication. Furthermore, a lack in induction of interferon-related gene expression characterised the main difference between the highly pathogenic coronaviruses and low pathogenic viruses HCoV-229E and HCoV-OC43.

Conclusion: Our results demonstrate a previously unknown suppression of a host response gene set by SARS-CoV-2 and confirm a difference in interferon-related gene expression between highly pathogenic and low pathogenic coronaviruses.

Keywords: RNA sequencing; SARS‐CoV‐2; coronavirus; immediate early genes; primary airway epithelial cells.