Human genes with codon usage bias similar to that of the nonstructural protein 1 gene of influenza A viruses are conjointly involved in the infectious pathogenesis of influenza A viruses

Abstract

Molecular mechanisms of the non-structural protein 1 (NS1) in influenza A-induced pathological changes remain ambiguous. This study explored the pathogenesis of human infection by influenza A viruses (IAVs) through identifying human genes with codon usage bias (CUB) similar to NS1 gene of these viruses based on the relative synonymous codon usage (RSCU). CUB of the IAV subtypes H1N1, H3N2, H3N8, H5N1, H5N2, H5N8, H7N9 and H9N2 was analyzed and the correlation of RSCU values of NS1 sequences with those of the human genes was calculated. The CUB of NS1 was uneven and codons ending with A/U were preferred. The ENC-GC3 and neutrality plots suggested natural selection as the main determinant for CUB. The RCDI, CAI and SiD values showed that the viruses had a high degree of adaptability to human. A total of 2155 human genes showed significant RSCU-based correlation (p < 0.05 and r > 0.5) with NS1 coding sequences and was considered as human genes with CUB similar to NS1 gene of IAV subtypes. Differences and similarities in the subtype-specific human protein-protein interaction (PPI) networks and their functions were recorded among IAVs subtypes, indicating that NS1 of each IAV subtype has a specific pathogenic mechanism. Processes and pathways involved in influenza, transcription, immune response and cell cycle were enriched in human gene sets retrieved based on the CUB of NS1 gene of IAV subtypes. The present work may advance our understanding on the mechanism of NS1 in human infections of IAV subtypes and shed light on the therapeutic options.

Keywords: Adaptation to host; Codon usage bias; Influenza A virus; NS1 human interactome; Nonstructural protein 1; Relative synonymous codon usage.

Fig. 1

The relative synonymous codon usage (RSCU) values of the NS1 coding sequences of IAV subtypes

Fig. 2

The effective number of codons (ENC) values of NS1 of IAV subtypes. The egdes of the inset network indicates the distribution of adjusted p-values among the compared node groups of IAV subtypes

Fig. 3

Principal component analysis (PCA) for NS1 of IAV subtypes based on the RSCU values. A PCA based on the RSCU values of NS1 of IAV subtypes; B PCA based on the RSCU values of NS1 of IAV subtypes and RSCU values of all genes of H. sapiens

Fig. 4

ENC-plot analysis of NS1 of IAV subtypes. ENC-plot analysis of the NS1, with ENC, plotted against GC3s of H1N1, H3N2, H3N8, H5N1, H5N2, H5N8, H7N9, and H9N2 was generated. The red curve represents the expected ENC curve when the CUB is determined by the GC3s composition only. The black dots represent the distribution of ENC values of NS1of AIV subtypes

Fig. 5

Neutrality plot analysis of GC3s against GC12s for all the coding sequences based on NS1 of IAV subtypes. A Pearson correlation analysis between the GC3s and GC12s of H1N1, H3N2, H3N8, H5N1, H5N2, H5N8, H7N9, and H9N2. B Neutrality plots of H1N1, H3N2, H3N8, H5N1, H5N2, H5N8, H7N9, and H9N2

Fig. 6

The PR2 plots of NS1 of IAV subtypes. The AT [A3%/(A3% + T3%)] and GC [G3%/ (G3% + C3%)] bias of H1N1, H3N2, H3N8, H5N1, H5N2, H5N8, H7N9, and H9N2 were plotted. The center of the plot (both the coordinates is 0.5) indicates a position where there is no bias

Fig. 7

Adaptation analysis of NS1 of IAV subtypes. A The codon adaptation index (CAI) analysis of IAV NS1. B The RCDI values of IAV NS1. C The SCUO analysis of IAV subtypes. D The similarity index (SiD) analysis of IAV NS1. E Heatmap showing the Pearson correlation between the ENC, CAI, RCDI and SCUO values of NS1 coding sequences of H1N1, H3N2, H3N8, H5N1, H5N2, H5N8, H7N9, and H9N2. The egdes of the inset network indicates the distribution of adjusted p-values among the compared node groups of IAV subtypes in A–C. Statistical analysis was not applicable to D

Fig. 8

Functional enrichment analysis of human genes with CUB similar to that of NS1 gene of IAV subtypes. The GO and pathway functional enrichment analysis was performed and the top 10 terms were visualized for each GO categories and pathway category

Fig. 9

Hub gene subnetwork extracted from the protein–protein interaction (PPI) network of the human genes with CUB similar to that of NS1 of IAV subtypes. A The PPI network based on the top-2000 (based on Pearson correlation) human genes with CUB similar to that of NS1 of IAV subtypes was constructed and the MCODE plugin was used for extracting the hub gene subnetworks and the hub gene cluster with the highest score was visualized. B Functional enrichment analysis of hub genes extracted from the human genes with CUB similar to that of NS1 of IAV subtypes. The GO and pathway functional enrichment analysis was performed and the top 10 terms were visualized for each GO categories and pathway category

Fig. 10

Similarities and differences of the PPI networks of human genes with CUB similar to that of NS1 coding sequences from different IAV subtypes. A Intersection analysis of the different PPI networks of human genes with CUB similar to that of NS1 coding sequences from each IAV subtype. B Networks of hub genes of the different PPI networks of human genes with CUB similar to that of NS1 coding sequences from each IAV subtype