Decoding Viral Signatures: Comparative Transcriptomics of SARS-CoV-2, Influenza A, and RSV Reveals Virus-Specific Host Responses

Background: Respiratory viral infections caused by SARS-CoV-2, Influenza A virus (IAV), and Respiratory Syncytial Virus (RSV) represent significant public health threats with overlapping clinical presentations but potentially distinct molecular pathogenesis. Understanding virus-specific versus shared host transcriptomic responses is critical for developing targeted therapeutics and diagnostic biomarkers. Methods: We performed comparative differential expression analysis using publicly available RNA-sequencing data (GSE147507) from human airway epithelial cells infected with SARS-CoV-2 (n=21), IAV (n=10), or RSV (n=5) compared to mock controls (n=29) at 24 hours post-infection. Statistical analysis employed independent t-tests with Benjamini-Hochberg FDR correction (|Log₂FC| > 1, adjusted p < 0.05). Comparative analyses included Venn diagrams, hierarchical clustering, and volcano plot visualizations. Results: We identified 125 differentially expressed genes (DEGs) for SARS-CoV-2, 294 for IAV, and 121 for RSV. Strikingly, only 3 genes were commonly upregulated across all three viruses, representing 0.6% of total unique DEGs (n=492). Pairwise overlaps were minimal: 5 genes (COVID-IAV), 8 genes (COVID-RSV), and 29 genes (IAV-RSV). Virus-specific signatures comprised 109 genes (87.2% for SARS-CoV-2), 257 genes (87.4% for IAV), and 81 genes (66.9% for RSV). Hierarchical clustering revealed distinct expression patterns with minimal inter-viral overlap, demonstrating predominantly pathogen-specific rather than universal antiviral responses. Conclusions: Our findings demonstrate that respiratory viral infections elicit largely virus-specific transcriptional programs with minimal shared immune signatures. These results have important implications for precision antiviral therapeutic development and molecular diagnostic strategies.