Network perturbation analysis of gene transcriptional profiles reveals protein targets and mechanism of action of drugs and influenza A viral infection

Noh, Heeju; Shoemaker, Jason E; Gunawan, Rudiyanto

We (27) (28) (29) (30) . We employed ProTINA to compute the overall protein target scores using the gene expression data of Calu-3 from the four studies above, by averaging the scores from the early phase of the influenza infection between 0 and 12 h. We checked the target predictions of ProTINA against the findings from a genome-wide co-immunoprecipitation analysis of host and viral protein interactions (49) . More specifically, the aforementioned study reported 1292 host proteins that co-immunoprecipitated with viral proteins of influenza A/WSN/33 using human embryonic kidney cells (HEK293). Despite the discrepancy in the cell types and influenza viral strains between the co-immunoprecipitation analysis and the gene expression profiling, influenza A viruses share similar features and common protein interac- tions (59, 60) . Besides ProTINA, we also evaluated the accuracy of viral target predictions from DeMAND and DE for the same dataset. Figure 5 gives the receiver operating characteristic (ROC) curves of the target predictions from ProTINA, DeMAND and DE analysis. ProTINA outperformed the two other methods, providing the highest AUROC (ProTINA: 0.76 versus demand: 0.69 and DE: 0.65). We further performed a gene set enrichment analysis (GSEA) for the target predictions from each of the methods (see Materials and Methods) to elucidate the key pathways involved in the viral infection and the accompanying host response. The results of the GSEA are summarized in Figure 6 . Both DeMAND and DE target predictions were enriched for only a few pathways (q-value < 0.01), while ProTINA prediction had a much higher number of overrepresented pathways.