title: Kinome siRNA screen identifies novel cell-type specific dengue host target genes.
abstract: Dengue is a global emerging infectious disease, with no specific treatment available. To identify novel human host cell targets important for dengue virus infection and replication, an image-based high-throughput siRNA assay screening of a human kinome siRNA library was conducted using human hepatocyte cell line Huh7 infected with a recent dengue serotype 2 virus isolate BR DEN2 01-01. In the primary siRNA screening of 779 kinase-related genes, knockdown of 22 genes showed a reduction in DENV-2 infection. Conversely, knockdown of 8 genes enhanced viral infection. To assess host cell specificity, the confirmed hits were tested in the DENV-infected monocytic cell line U937. While the expression of EIF2AK3, ETNK2 and SMAD7 was regulated in both cell lines after infection, most kinases were hepatocyte-specific. Monocytic cells represent initial targets of infection and an antiviral treatment targeting these cells is probably most effective to reduce initial viral load. In turn, infection of the liver could contribute to pathogenesis, and the novel hepatocyte-specific human targets identified here could be important for dengue infection and pathogenesis.
authors.affiliation: Discovery Biology Group, Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, South Korea.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Kwon
authors.affiliation: Discovery Biology Group, Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, South Korea.
authors.forename: Jinyeong
authors.initials: J
authors.lastname: Heo
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Groove, #03-06 Immunos, Singapore 138648, Singapore.
authors.forename: Hazel E E
authors.initials: HE
authors.lastname: Wong
authors.affiliation: Center for Neglected Diseases Drug Discovery, Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, South Korea.
authors.forename: Deu John M
authors.initials: DJ
authors.lastname: Cruz
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Groove, #03-06 Immunos, Singapore 138648, Singapore.
authors.forename: Sumathy
authors.initials: S
authors.lastname: Velumani
authors.affiliation: Center for Neglected Diseases Drug Discovery, Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, South Korea.
authors.forename: Camila T
authors.initials: CT
authors.lastname: da Silva
authors.affiliation: Instituto Carlos Chagas, Fundação Oswaldo Cruz Paraná (ICC/FIOCRUZ-PR), Curitiba, Paraná, Brazil.
authors.forename: Ana Luiza P
authors.initials: AL
authors.lastname: Mosimann
authors.affiliation: Instituto Carlos Chagas, Fundação Oswaldo Cruz Paraná (ICC/FIOCRUZ-PR), Curitiba, Paraná, Brazil.
authors.forename: Claudia N
authors.initials: CN
authors.lastname: Duarte Dos Santos
authors.affiliation: Center for Neglected Diseases Drug Discovery, Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, South Korea. Electronic address: lucio.freitasjunior@lnbio.cnpem.br.
authors.forename: Lucio H
authors.initials: LH
authors.lastname: Freitas-Junior
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Groove, #03-06 Immunos, Singapore 138648, Singapore. Electronic address: katja_fink@immunol.a-star.edu.sg.
authors.forename: Katja
authors.initials: K
authors.lastname: Fink
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003715:Dengue / Q000628:therapy; D003716:Dengue Virus / Q000254:growth & development*; D022781:Hepatocytes / Q000821:virology; D057166:High-Throughput Screening Assays; D054884:Host-Pathogen Interactions; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology*; D051906:Smad7 Protein / Q000235:genetics; D014779:Virus Replication / Q000235:genetics*; D019892:eIF-2 Kinase / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D034741:RNA, Small Interfering; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C020125:ethanolamine kinase; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase
keywords: Dengue; Host cell targets; Kinase; siRNA