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

The common enriched pathways among ProTINA, De-MAND and DE (top of Figure 6 ) included known mechanisms related to viral entry, replication and assembly, including endocytosis (61) , protein processing in endoplasmic reticulum (62) , ubiquitin mediated proteolysis (63, 64) and RIG-I-like receptor signaling pathway (65, 66) . Both ProTINA and DE analysis indicated the modulation of host cell cycle (67) , mRNA surveillance (68) and DNA damage response (69) . Only ProTINA prediction was significantly enriched for focal adhesion and actin cytoskeleton, which have been shown to regulate influenza virus entry at the early stage of infection (70) . In addition, ProTINA target predictions were also enriched for a broad set of host response pathways to viral infection, including host defense mechanism (e.g. T-and B-cell receptor pathways, phagocytosis, leukocyte migration, chemokine signaling pathways), DNA damage repair (e.g. nucleotide excision repair, p53 signaling pathway, homologous recombination) and apop- tosis. As several influenza proteins are known to interfere with interferon production (which in turn regulates several cytokines) (65, 66) , these findings suggest that, overall, ProTINA provided a broader picture of the early events in the influenza A viral infection, than DeMAND and DE analysis.