Abstract
Human coronaviruses (HCoVs) cause mild to severe respiratory infection. Most of the common cold illnesses are caused by one of four HCoVs, namely HCoV-229E, HCoV-NL63, HCoV-HKU1 and HCoV-OC43. Several studies have applied global transcriptomic methods to understand host responses to HCoV infection, with most studies focusing on the pandemic severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV) and the newly emerging SARS-CoV-2. In this study, Next Generation Sequencing was used to gain new insights into cellular transcriptomic changes elicited by alphacoronavirus HCoV-229E. HCoV-229E-infected MRC-5 cells showed marked downregulation of superpathway of cholesterol biosynthesis and eIF2 signaling pathways. Moreover, upregulation of cyclins, cell cycle control of chromosomal replication, and the role of BRCA1 in DNA damage response, alongside downregulation of the cell cycle G1/S checkpoint, suggest that HCoV-229E may favors S phase for viral infection. Intriguingly, a significant portion of key factors of cell innate immunity, interferon-stimulated genes (ISGs) and other transcripts of early antiviral response genes were downregulated early in HCoV-229E infection. On the other hand, early upregulation of the antiviral response factor Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) was observed. APOBEC3B cytidine deaminase signature (C-to-T) was previously observed in genomic analysis of SARS-CoV-2 but not HCoV-229E. Higher levels of C-to-T mutations were found in countries with high mortality rates caused by SARS-CoV-2. APOBEC activity could be a marker for new emerging CoVs. This study will enhance our understanding of commonly circulating HCoVs and hopefully provide critical information about still-emerging coronaviruses.
Highlights
Human coronaviruses (HCoVs), which are enveloped, positive single-stranded RNA (+ssRNA) viruses belonging to the Coronaviridae family, are associated with a wide spectrum of respiratory diseases [1, 2]
At early stages of infection, considerable downregulation of the elongation initiation factor 2 (eIF2) signaling pathway was observed in MRC-5 cells, a trend which increased as infection progressed (Fig 2B-I)
This study sought to shed light on host transcriptome responses to common infecting HCoVs, using next generation sequencing (NGS) and bioinformatics tools. It aimed to examine major transcriptomic changes occurring over several cycles of HCoV-229E infection in human host cells
Summary
Human coronaviruses (HCoVs), which are enveloped, positive single-stranded RNA (+ssRNA) viruses belonging to the Coronaviridae family, are associated with a wide spectrum of respiratory diseases [1, 2]. Coronaviruses have an exceptionally large ~30 kb genome in polycistronic organization and engage a unique transcription mechanism to generate mRNA [11] They possess many non-structural proteins (NSPs) that appear to have multiple functions in RNA processing, facilitating viral entry, gene expression and virus release [10]. Many +ssRNA viruses use diverse strategies to subvert and exploit host protein synthesis [12], with one central strategy involving inactivation of the elongation initiation complex by manipulating kinase activities. Some coronaviruses have evolved to counteract the dsRNA-activated protein kinase (PKR), which prevents translation by phosphorylating elongation initiation factor 2 (eIF2) and upregulating antiviral gene expression, including the production of interferons (IFNs) [10, 14]. Several additional innate immune receptors involved in recognizing RNA viruses activate interferon-stimulated genes (ISGs) and other cellular factors which fight the viral intruders [15]
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