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Network-guided Discovery of Influenza Virus Replication Host Factors

By Emily E Ackerman, Eiryo Kawakami, Manami Katoh, Tokiko Watanabe, Shinji Watanabe, Yuriko Tomita, Tiago J. Lopes, Yukiko Matsuoka, Hiroaki Kitano, Jason E. Shoemaker, Yoshihiro Kawaoka

Posted 13 Jun 2018
bioRxiv DOI: 10.1101/344861 (published DOI: 10.1128/mbio.02002-18)

The position of host factors required for viral replication within a human protein-protein interaction (PPI) network can be exploited to identify drug targets that are robust to drug-mediated selective pressure. Host factors can physically interact with viral proteins, be a component of pathways regulated by viruses (where proteins themselves do not interact with viral proteins) or be required for viral replication but unregulated by viruses. Here, we demonstrate a method of combining a human PPI network with virus-host protein interaction data to improve antiviral drug discovery for influenza viruses by identifying target host proteins. Network analysis shows that influenza virus proteins physically interact with host proteins in network positions significant for information flow. We have isolated a subnetwork of the human PPI network which connects virus-interacting host proteins to host factors that are important for influenza virus replication without physically interacting with viral proteins. The subnetwork is enriched for signaling and immune processes. Selecting proteins based on network topology within the subnetwork, we performed an siRNA screen to determine if the subnetwork was enriched for virus replication host factors and if network position within the subnetwork offers an advantage in prioritization of drug targets to control influenza virus replication. We found that the subnetwork is highly enriched for target host proteins - more so than the set of host factors that physically interact with viral proteins. Our findings demonstrate that network positions are a powerful predictor to guide antiviral drug candidate prioritization.

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