title: Influenza virus-host interactome screen as a platform for antiviral drug development.
abstract: Host factors required for viral replication are ideal drug targets because they are less likely than viral proteins to mutate under drug-mediated selective pressure. Although genome-wide screens have identified host proteins involved in influenza virus replication, limited mechanistic understanding of how these factors affect influenza has hindered potential drug development. We conducted a systematic analysis to identify and validate host factors that associate with influenza virus proteins and affect viral replication. After identifying over 1,000 host factors that coimmunoprecipitate with specific viral proteins, we generated a network of virus-host protein interactions based on the stage of the viral life cycle affected upon host factor downregulation. Using compounds that inhibit these host factors, we validated several proteins, notably Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1) and JAK1, as potential antiviral drug targets. Thus, virus-host interactome screens are powerful strategies to identify targetable host factors and guide antiviral drug development.
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Tokiko
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Eiryo
authors.initials: E
authors.lastname: Kawakami
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Shoemaker
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Tiago J S
authors.initials: TJ
authors.lastname: Lopes
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan; The Systems Biology Institute, Minato-ku, Tokyo 108-0071, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Matsuoka
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kozuka-Hata
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA.
authors.forename: Takeo
authors.initials: T
authors.lastname: Gorai
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kuwahara
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Takeda
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nagata
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Takano
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kiso
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sakai-Tagawa
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Katsura
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nonaka
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Fujii
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Fujii
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugita
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Noda
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Goto
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukuyama
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan; Laboratory of Veterinary Microbiology, Department of Veterinary Sciences, University of Miyazaki, Miyazaki 889-2192, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Neumann
authors.affiliation: Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oyama
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan; The Systems Biology Institute, Minato-ku, Tokyo 108-0071, Japan; Laboratory for Disease Systems Modeling, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan; Okinawa Institute of Science and Technology, Onna-son, Okinawa 904-0495, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kitano
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA; Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan. Electronic address: kawaokay@svm.vetmed.wisc.edu.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping / Q000379:methods*; D060066:Protein Interaction Maps / Q000187:drug effects*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; C120445:GBF1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D014764:Viral Proteins; C507904:JAK1 protein, human; D053613:Janus Kinase 1