Uncovering the Pathophysiological Pattern of Expression from Integrated Analysis across Uniformly Processed RNA...

Area of Science:

• Genomics and Molecular Biology
• Infectious Diseases
• Translational Medicine

Background:

• Millions suffer from post-acute sequelae of SARS-CoV-2 infection (PASC), but molecular mechanisms of acute COVID-19 and chronic PASC remain unclear.
• Understanding these mechanisms is crucial for developing effective diagnostics and treatments for the diverse spectrum of COVID-19.

Purpose of the Study:

• To perform an integrative transcriptomic analysis of COVID-19 progression from acute infection to PASC.
• To identify molecular signatures distinguishing different phases of SARS-CoV-2 infection.
• To establish a molecular framework for precision diagnosis and monitoring of COVID-19.

Main Methods:

• Integrative transcriptomic analysis of three independent RNA-seq datasets (n=142) covering health, acute severe infection, PASC, and mortality.
• Utilized a containerized analytical pipeline for uniform data processing, including quantification and differential gene expression analysis.
• Employed pathway signature analysis to identify core differentially expressed genes distinguishing disease phases.

Main Results:

• Acute severe/critical COVID-19 showed enrichment of TNF-α signaling via NF-κB pathways, indicative of a cytokine storm.
• PASC patients exhibited dominant enrichment of Myc Targets V1 and Oxidative Phosphorylation pathways, suggesting cellular adaptation.
• Identified core differentially expressed genes that reliably distinguish disease phases, serving as potential objective biomarkers.

Conclusions:

• Established a molecular framework differentiating acute inflammatory and chronic metabolic phases of COVID-19.
• TNF-α/NF-κB signatures can identify patients at risk for severe disease, while Myc/OXPHOS signatures aid objective PASC diagnosis.
• The integrative analytical framework supports precision medicine applications beyond COVID-19.