Network-Guided Discovery of Influenza Virus Replication Host Factors

ABSTRACT The positions 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 vi...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	drug targets influenza protein-protein interactions virus-host interactions Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1d0453a0ea7a40cba31ae3384b1f2bc5
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spelling	oai:doaj.org-article:1d0453a0ea7a40cba31ae3384b1f2bc52021-11-15T15:52:19ZNetwork-Guided Discovery of Influenza Virus Replication Host Factors10.1128/mBio.02002-182150-7511https://doaj.org/article/1d0453a0ea7a40cba31ae3384b1f2bc52018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02002-18https://doaj.org/toc/2150-7511ABSTRACT The positions 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 virus-regulated pathways (where proteins do not interact with viral proteins), or be required for viral replication but unregulated by viruses. Here, we demonstrate a method of combining human PPI networks with virus-host PPI data to improve antiviral drug discovery for influenza viruses by identifying target host proteins. Analysis shows that influenza virus proteins physically interact with host proteins in network positions significant for information flow, even after the removal of known abundance-degree bias within PPI data. We have isolated a subnetwork of the human PPI network that 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 distinct from those associated with virus-interacting proteins. Selecting proteins based on subnetwork topology, we performed an siRNA screen to determine whether the subnetwork was enriched for virus replication host factors and whether 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. IMPORTANCE Integrating virus-host interactions with host protein-protein interactions, we have created a method using these established network practices to identify host factors (i.e., proteins) that are likely candidates for antiviral drug targeting. We demonstrate that interaction cascades between host proteins that directly interact with viral proteins and host factors that are important to influenza virus replication are enriched for signaling and immune processes. Additionally, we show that host proteins that interact with viral proteins are in network locations of power. Finally, we demonstrate a new network methodology to predict novel host factors and validate predictions with an siRNA screen. Our results show that integrating virus-host proteins interactions is useful in the identification of antiviral drug target candidates.Emily E. AckermanEiryo KawakamiManami KatohTokiko WatanabeShinji WatanabeYuriko TomitaTiago J. LopesYukiko MatsuokaHiroaki KitanoJason E. ShoemakerYoshihiro KawaokaAmerican Society for Microbiologyarticledrug targetsinfluenzaprotein-protein interactionsvirus-host interactionsMicrobiologyQR1-502ENmBio, Vol 9, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	drug targets influenza protein-protein interactions virus-host interactions Microbiology QR1-502
spellingShingle	drug targets influenza protein-protein interactions virus-host interactions Microbiology QR1-502 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 Network-Guided Discovery of Influenza Virus Replication Host Factors
description	ABSTRACT The positions 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 virus-regulated pathways (where proteins do not interact with viral proteins), or be required for viral replication but unregulated by viruses. Here, we demonstrate a method of combining human PPI networks with virus-host PPI data to improve antiviral drug discovery for influenza viruses by identifying target host proteins. Analysis shows that influenza virus proteins physically interact with host proteins in network positions significant for information flow, even after the removal of known abundance-degree bias within PPI data. We have isolated a subnetwork of the human PPI network that 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 distinct from those associated with virus-interacting proteins. Selecting proteins based on subnetwork topology, we performed an siRNA screen to determine whether the subnetwork was enriched for virus replication host factors and whether 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. IMPORTANCE Integrating virus-host interactions with host protein-protein interactions, we have created a method using these established network practices to identify host factors (i.e., proteins) that are likely candidates for antiviral drug targeting. We demonstrate that interaction cascades between host proteins that directly interact with viral proteins and host factors that are important to influenza virus replication are enriched for signaling and immune processes. Additionally, we show that host proteins that interact with viral proteins are in network locations of power. Finally, we demonstrate a new network methodology to predict novel host factors and validate predictions with an siRNA screen. Our results show that integrating virus-host proteins interactions is useful in the identification of antiviral drug target candidates.
format	article
author	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
author_facet	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
author_sort	Emily E. Ackerman
title	Network-Guided Discovery of Influenza Virus Replication Host Factors
title_short	Network-Guided Discovery of Influenza Virus Replication Host Factors
title_full	Network-Guided Discovery of Influenza Virus Replication Host Factors
title_fullStr	Network-Guided Discovery of Influenza Virus Replication Host Factors
title_full_unstemmed	Network-Guided Discovery of Influenza Virus Replication Host Factors
title_sort	network-guided discovery of influenza virus replication host factors
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/1d0453a0ea7a40cba31ae3384b1f2bc5
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_version_	1718427259558166528

Network-Guided Discovery of Influenza Virus Replication Host Factors

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