Ribosome-Profiling Reveals Restricted Post Transcriptional Expression of Antiviral Cytokines and Transcription Factors during SARS-CoV-2 Infection.

Marina R Alexander,Christina L Rootes,Andrew G D Bean,Aaron M Brice,Cameron R Stewart,Petrus Jansen Van Vuren,Leon Tribolet,Christopher Cowled

doi:10.3390/ijms22073392

Abstract

The global COVID-19 pandemic caused by SARS-CoV-2 has resulted in over 2.2 million deaths. Disease outcomes range from asymptomatic to severe with, so far, minimal genotypic change to the virus so understanding the host response is paramount. Transcriptomics has become incredibly important in understanding host-pathogen interactions; however, post-transcriptional regulation plays an important role in infection and immunity through translation and mRNA stability, allowing tight control over potent host responses by both the host and the invading virus. Here, we apply ribosome profiling to assess post-transcriptional regulation of host genes during SARS-CoV-2 infection of a human lung epithelial cell line (Calu-3). We have identified numerous transcription factors (JUN, ZBTB20, ATF3, HIVEP2 and EGR1) as well as select antiviral cytokine genes, namely IFNB1, IFNL1,2 and 3, IL-6 and CCL5, that are restricted at the post-transcriptional level by SARS-CoV-2 infection and discuss the impact this would have on the host response to infection. This early phase restriction of antiviral transcripts in the lungs may allow high viral load and consequent immune dysregulation typically seen in SARS-CoV-2 infection.

Highlights

Published: 25 March 2021Coronaviruses are enveloped positive sense RNA viruses with an exceptionally large genome encoding the structural proteins envelope (E), spike (S), membrane (M), and nucleocapsid (N), in addition to a plethora of non-structural and accessory proteins
Of the multiple organs that SARS-CoV-2 infects, viral load is highest in the lungs, and infection of this organ is a significant driver of pathogenesis [10]
In infected lung epithelial cells, these transcription factors activate transcription of genes which can be categorized into three groups. (i) Type I and III

Summary

Introduction

Published: 25 March 2021Coronaviruses are enveloped positive sense RNA viruses with an exceptionally large genome encoding the structural proteins envelope (E), spike (S), membrane (M), and nucleocapsid (N), in addition to a plethora of non-structural and accessory proteins. Infections with endemic human coronaviruses (e.g., 229E, NL63, OC43, and HKU1) cause a mild common cold, three novel coronaviruses have emerged from animal reservoirs in the 21st century, SARS-CoV, MERS and SARS-CoV-2 causing a fatal respiratory syndrome in 34%, 15%, and 3% of cases, respectively with SARS-CoV-2 being the most infectious [1]. The current COVID-19 pandemic caused by SARS-CoV-2 emerged in China in December. 2019 [2] and has since spread across the globe, causing more than 100 million confirmed cases and over 2.7 million deaths (https://covid19.who.int/ accessed on 24 March 2021). SARS-CoV-2 is adept at evading innate immunity [3], the naïve host’s primary defense against a newly emerged coronavirus. It does this using numerous structural and nonstructural proteins that inhibit interferon (IFN) production and function.

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Conclusion