Patient-based transcriptome-wide analysis identify interferon and ubiquination pathways as potential predictors of influenza A disease severity

Abstract

Background: The influenza A virus is an RNA virus that is responsible for seasonal epidemics worldwide with up to five million cases of severe illness and 500,000 deaths annually according to the World Health Organization estimates. The factors associated with severe diseases are not well defined, but more severe disease is more often seen among persons aged >65 years, infants, pregnant women, and individuals of any age with underlying health conditions.

Methodology/principal findings: Using gene expression microarrays, the transcriptomic profiles of influenza-infected patients with severe (N = 11), moderate (N = 40) and mild (N = 83) symptoms were compared with the febrile patients of unknown etiology (N = 73). We found that influenza-infected patients, regardless of their clinical outcomes, had a stronger induction of antiviral and cytokine responses and a stronger attenuation of NK and T cell responses in comparison with those with unknown etiology. More importantly, we found that both interferon and ubiquitination signaling were strongly attenuated in patients with the most severe outcomes in comparison with those with moderate and mild outcomes, suggesting the protective roles of these pathways in disease pathogenesis.

Conclusion/significances: The attenuation of interferon and ubiquitination pathways may associate with the clinical outcomes of influenza patients.

Figure 1. The numbers of differentially expressed transcripts (FDR 0.05, fold change >2) were observed in patients with mild and moderate influenza in comparison with OFI and severe patients.

The y-axis shows the number of differentially expressed transcripts in acute samples for each condition on the x-axis in comparison with their convalescent samples. Up-regulated genes in the acute phase are in blue, genes down-regulated in dark red.

Figure 2. Genes that were involved in Toll-like receptor signaling, IL-10 signaling, Role of PKR in Interferon Induction and Antiviral Response and NFkB signaling pathways.

The pathway names were shared between different groups but the activated genes in each pathway were different. Differentially expressed genes (FDR <0.05, fold change >2) were highlighted in grey.

Figure 3. Interferon signaling pathways was highly up-regulated in moderate and mild influenza patients but was attenuated in patients with severe outcome.

Up-regulated genes were highlighted in grey. IFNGR1 was the only gene that was up-regulated in severe patients while a large number of other genes were up-regulated in moderate and mild patients.

Figure 4. Genes that were involved in the most significantly down-regulated pathways such as Natural Killer Cell Signaling, Crosstalk between Dendritic Cells and Natural Killer Cells, CD28 Signaling in T Helper Cells, PKCθ Signaling in T Lymphocytes.

The pathway names were shared between different groups but the activated genes in each pathway were different. Differentially expressed genes (FDR <0.05, fold change >2) were highlighted in grey.

Figure 5. Difference in expression of transcripts in T cell and NK cell signaling pathways.

These transcripts were only down-regulated in patients with severe symptoms but not in OFI, mild and moderate disease (*: P≤0.05).