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. 2011 Jun 8:8:285.
doi: 10.1186/1743-422X-8-285.

Cellular transcriptional profiling in human lung epithelial cells infected by different subtypes of influenza A viruses reveals an overall down-regulation of the host p53 pathway

Olivier Terrier  1 , Laurence Josset, Julien Textoris, Virginie Marcel, Gaëlle Cartet, Olivier Ferraris, Catherine N'guyen, Bruno Lina, Jean-Jacques Diaz, Jean-Christophe Bourdon, Manuel Rosa-Calatrava
Affiliations

Cellular transcriptional profiling in human lung epithelial cells infected by different subtypes of influenza A viruses reveals an overall down-regulation of the host p53 pathway

Olivier Terrier et al. Virol J. .

Abstract

Background: Influenza viruses can modulate and hijack several cellular signalling pathways to efficiently support their replication. We recently investigated and compared the cellular gene expression profiles of human lung A549 cells infected by five different subtypes of human and avian influenza viruses (Josset et al. Plos One 2010). Using these transcriptomic data, we have focused our analysis on the modulation of the p53 pathway in response to influenza infection.

Results: Our results were supported by both RT-qPCR and western blot analyses and reveal multiple alterations of the p53 pathway during infection. A down-regulation of mRNA expression was observed for the main regulators of p53 protein stability during infection by the complete set of viruses tested, and a significant decrease in p53 mRNA expression was also observed in H5N1 infected cells. In addition, several p53 target genes were also down-regulated by these influenza viruses and the expression of their product reduced.

Conclusions: Our data reveal that influenza viruses cause an overall down-regulation of the host p53 pathway and highlight this pathway and p53 protein itself as important viral targets in the altering of apoptotic processes and in cell-cycle regulation.

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Figures

Figure 1
Figure 1
Summary of genes expressed in response to H1N1, H3N2, H5N1, H5N2 and H7N1 viral infection. A. Genes significantly regulated (SAM, FDR = 10%) in response to the different influenza viruses compared to mock infection at 24 hpi are shown. B. Venn-diagram showing the genes co-regulated by several viruses
Figure 2
Figure 2
Significantly enriched GO Biological Processes (p-value < 0.01) common to H3N2, H5N1, H5N2 and H7N1 specific signatures. Terms related to the p53 pathway are highlighted in grey.
Figure 3
Figure 3
Transcriptional regulation of the genes belonging to the p53 signalling pathway (IPA canonical pathway) during influenza viral infection. Mean fold changes of the genes encoding regulators and targets of p53 that were differentially expressed by at least one virus, calculated as Log2(Mean expression levels in infected samples) - Log2(Mean expression levels in mock samples) and overlaid on the pathway in green for downregulated genes (FC < 0), and red for upregulated genes (FC > 0). Fold changes in each group of samples are depicted in the heat maps and were used to cluster hierarchically both samples and genes. Genes considered significant for each virus with the SAM procedure are indicated by a white X on the heat maps.
Figure 4
Figure 4
A. Validation of microarray data by RT-qPCR. The measured ratio change of p53 mRNA levels was subject to statistical analysis (student t-test, *** p-value < 0.001). B. p53 protein levels revealed by western blot. C. Relative protein levels (RPL) measured by densitometry analysis.
Figure 5
Figure 5
Validation of microarray data by RT-qPCR and western blot: p53 target genes, (A) p21, (B) Bax, (C)Bcl-XL. (*, ** and *** correspond to p-values <0.05, <0,005, <0.001, respectively).
Figure 6
Figure 6
Comparison of viral titres (copies M/mL) produced in HCT116 p53 +/+ or -/- infected with H3N2 A/Moscow/10/99, calculated by RT-qPCR of M genome copies released in the supernatants.
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