Viral and Host Transcriptomes in SARS-CoV-2-Infected Human Lung Cells

Area of Science:

• Virology and Molecular Biology
• Transcriptomics
• Host-Pathogen Interactions

Background:

• Coronaviruses utilize discontinuous RNA synthesis guided by transcription-regulating sequences (TRSs).
• The precise RNA synthesis strategy and gene expression dynamics of SARS-CoV-2 remain incompletely understood.
• Host metabolic dysregulation and cytokine storm are critical aspects of SARS-CoV-2 pathogenesis.

Purpose of the Study:

• To elucidate the core transcription-regulating sequence (TRS) governing SARS-CoV-2 discontinuous RNA synthesis.
• To characterize the time-scaled transcriptome of SARS-CoV-2, detailing viral gene expression levels.
• To investigate host transcriptional responses, including metabolic pathways and cytokine activation, during SARS-CoV-2 infection.

Main Methods:

• Generation of a time-scaled, gene-comparable transcriptome for SARS-CoV-2.
• Analysis of viral RNA synthesis, distinguishing transcription from genome replication.
• Assessment of host pathway enrichment and cytokine activation patterns.

Main Results:

• Identified ACGAAC as the core TRS dictating SARS-CoV-2 discontinuous RNA synthesis.
• Demonstrated that viral transcription, not replication, is the predominant RNA synthesis activity.
• Revealed nucleocapsid gene as most highly expressed, while envelope gene expression is lowest; host metabolism (cholesterol, valine) and cytokines are significantly dysregulated.

Conclusions:

• The ACGAAC sequence is crucial for SARS-CoV-2 RNA synthesis, providing a holistic view of the process.
• SARS-CoV-2 infection profoundly impacts host metabolism and triggers early cytokine activation, preceding major viral RNA synthesis.
• Findings offer insights into viral gene expression and host responses, potentially guiding novel therapeutic strategies against SARS-CoV-2.