A dual controllability analysis of influenza virus-host protein-protein interaction networks for antiviral drug target discovery

Ackerman, Emily E.; Alcorn, John F.; Hase, Takeshi; Shoemaker, Jason E.

The 24 proteins identified by the global controllability analysis show promise as indicators of regulatory roles specific to the infected state. All global proteins are IAV interacting and driver proteins, a high distinction which demonstrates a significant importance to network information flow marked by significantly higher betweenness in the VIN than even driver proteins that are not IAV interacting. Additionally, all global proteins have no importance to network flow in the HIN (betweenness = 0) ( Table 4) , suggesting their role in network structure "turns on" after the onset of infection. It is noteworthy that PRDX1 has been implicated in respiratory syncytial virus (RSV) [58] , a lower respiratory tract infection that is often associated with influenza virus [59] . Though the number of global proteins identified in existing siRNA screening data is not statistically significant, it should be noted that siRNA screens cover only the partial genome. As such, this type of analysis could be used to direct future experimental studies to save time, money, and effort. IPA analysis reveals that some of the identified proteins hold roles in mRNA processing, an integral part of the influenza virus' ability to spread through processing its own RNA using host machinery [60] . The global protein network is centered around NF-kB, which is implicated in host immunity with evidence that the virus directly inhibits NF-kB activity [61, 62] . The interferon regulating roles of proteins in a high number of both identified sets (all 11 changing MIS proteins and 20 of 24 global-identified proteins) speak to their responsibility in controlling infection. PPA1 appears as downregulated in 63 studies and HNRNPA0 appears as downregulated in 20 studies when treated with interferon compared to a control, solidifying their involvement in the host immune response. In total, this evidence suggests that controllability analyses hold power as predictors for important regulators of the host response to influenza infection and, therefore, hold power for drug target prediction.