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学科主题临床医学
A Genetic Screen Identifies Interferon-alpha Effector Genes Required to Suppress Hepatitis C Virus Replication
Fusco, Dahlene N.1; Brisac, Cynthia1; John, Sinu P.2,12; Huang, Yi-Wen3,4,5; Chin, Christopher R.6,12; Xie, Tiao7; Zhao, Hong8; Jilg, Nikolaus1; Zhang, Leiliang9,10; Chevaliez, Stephane1,11; Wambua, Daniel1; Lin, Wenyu1; Peng, Lee1; Chung, Raymond T.1; Brass, Abraham L.6,12
关键词Treatment Gene Regulation Virology Mechanism
刊名GASTROENTEROLOGY
2013-06-01
DOI10.1053/j.gastro.2013.02.026
144期:7页:1438-U210
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Gastroenterology & Hepatology
资助者NIH ; American Association for the Study of Liver Disease ; ANRS (French National Agency for Research on AIDS and Viral Hepatitis) ; Gilead ; NIH ; American Association for the Study of Liver Disease ; ANRS (French National Agency for Research on AIDS and Viral Hepatitis) ; Gilead
研究领域[WOS]Gastroenterology & Hepatology
关键词[WOS]RAT-LIVER ; PATHWAYS ; PROTEINS ; CELLS ; EXPRESSION ; COFACTOR ; GAMMA
英文摘要

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease. Interferon-alpha (IFN alpha) is an important component of anti-HCV therapy; it up-regulates transcription of IFN-stimulated genes, many of which have been investigated for their antiviral effects. However, all of the genes required for the antiviral function of IFN alpha (IFN effector genes [IEGs]) are not known. IEGs include not only IFN-stimulated genes, but other nontranscriptionally induced genes that are required for the antiviral effect of IFN alpha. In contrast to candidate approaches based on analyses of messenger RNA (mRNA) expression, identification of IEGs requires a broad functional approach. METHODS: We performed an unbiased genome-wide small interfering RNA screen to identify IEGs that inhibit HCV. Huh7.5.1 hepatoma cells were transfected with small interfering RNAs incubated with IFN alpha and then infected with JFH1 HCV. Cells were stained using HCV core antibody, imaged, and analyzed to determine the percent infection. Candidate IEGs detected in the screen were validated and analyzed further. RESULTS: The screen identified 120 previously unreported IEGs. From these, we more fully evaluated the following: asparagine-linked glycosylation 10 homolog (yeast, alpha-1,2-glucosyltransferase); butyrylcholinesterase; dipeptidylpeptidase 4 (CD26, adenosine deaminase complexing protein 2); glucokinase (hexokinase 4) regulator; guanylate cyclase 1, soluble, beta 3; MYST histone acetyltransferase 1; protein phosphatase 3 (formerly 2B), catalytic subunit, beta isoform; peroxisomal proliferator-activated receptor-gamma-DBD-interacting protein 1; and solute carrier family 27 (fatty acid transporter), member 2; and demonstrated that they enabled IFN alpha-mediated suppression of HCV at multiple steps of its life cycle. Expression of these genes had more potent effects against flaviviridae because a subset was required for IFN alpha to suppress dengue virus but not influenza A virus. In addition, many of the host genes detected in this screen (92%) were not transcriptionally stimulated by IFN alpha; these genes represent a heretofore unknown class of non-IFN-stimulated gene IEGs. CONCLUSIONS: We performed a whole-genome loss-of-function screen to identify genes that mediate the effects of IFN alpha against human pathogenic viruses. We found that IFN alpha restricts HCV via actions of general and specific IEGs.

语种英语
所属项目编号U19 AI082630 ; 1R01AI091786
资助者NIH ; American Association for the Study of Liver Disease ; ANRS (French National Agency for Research on AIDS and Viral Hepatitis) ; Gilead ; NIH ; American Association for the Study of Liver Disease ; ANRS (French National Agency for Research on AIDS and Viral Hepatitis) ; Gilead
WOS记录号WOS:000319498500027
引用统计
被引频次:24[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/52543
专题北京大学第一临床医学院_感染疾病科
作者单位1.Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA
2.NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA
3.Natl Taiwan Univ, Coll Med, Dept Internal Med, Taipei, Taiwan
4.Cathay Gen Hosp, Med Ctr, Hosp Liver Ctr, Taipei, Taiwan
5.Taipei Med Univ, Sch Med, Taipei, Taiwan
6.Univ Massachusetts, Sch Med, Dept Microbiol & Physiol Syst, Worcester, MA 01605 USA
7.Harvard Univ, Sch Med, Image & Data Anal Core, Boston, MA USA
8.Peking Univ, Hosp Beijing 1, Dept Infect Dis, Beijing, Peoples R China
9.Chinese Acad Med Sci, Inst Pathogen Biol, MOH Key Lab Syst Biol Pathogens, Beijing 100730, Peoples R China
10.Peking Union Med Coll, Beijing 100021, Peoples R China
11.Univ Paris Est, Dept Virol, Hosp Univ Henri Mondor, Creteil, France
12.Ragon Inst, Charlestown, MA USA
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GB/T 7714
Fusco, Dahlene N.,Brisac, Cynthia,John, Sinu P.,et al. A Genetic Screen Identifies Interferon-alpha Effector Genes Required to Suppress Hepatitis C Virus Replication[J]. GASTROENTEROLOGY,2013,144(7):1438-U210.
APA Fusco, Dahlene N..,Brisac, Cynthia.,John, Sinu P..,Huang, Yi-Wen.,Chin, Christopher R..,...&Brass, Abraham L..(2013).A Genetic Screen Identifies Interferon-alpha Effector Genes Required to Suppress Hepatitis C Virus Replication.GASTROENTEROLOGY,144(7),1438-U210.
MLA Fusco, Dahlene N.,et al."A Genetic Screen Identifies Interferon-alpha Effector Genes Required to Suppress Hepatitis C Virus Replication".GASTROENTEROLOGY 144.7(2013):1438-U210.
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