Identification of five interferon-induced cellular proteins that inhibit west nile virus and dengue virus infections.
Interferons (IFNs) are key mediators of the host innate antiviral immune response. To identify IFN-stimulated genes (ISGs) that instigate an antiviral state against two medically important flaviviruses, West Nile virus (WNV) and dengue virus (DENV), we tested 36 ISGs that are commonly induced by IFN-alpha for antiviral activity against the two viruses. We discovered that five ISGs efficiently suppressed WNV and/or DENV infection when they were individually expressed in HEK293 cells. Mechanistic analyses revealed that two structurally related cell plasma membrane proteins, IFITM2 and IFITM3, disrupted early steps (entry and/or uncoating) of the viral infection. In contrast, three IFN-induced cellular enzymes, viperin, ISG20, and double-stranded-RNA-activated protein kinase, inhibited steps in viral proteins and/or RNA biosynthesis. Our results thus imply that the antiviral activity of IFN-alpha is collectively mediated by a panel of ISGs that disrupt multiple steps of the DENV and WNV life cycles.
Jiang
Dong
D
Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania 18902, USA.
Weidner
Jessica M
JM
Qing
Min
M
Pan
Xiao-Ben
XB
Guo
Haitao
H
Xu
Chunxiao
C
Zhang
Xianchao
X
Birk
Alex
A
Chang
Jinhong
J
Shi
Pei-Yong
PY
Block
Timothy M
TM
Guo
Ju-Tao
JT
D002460:Cell Line; D003716:Dengue Virus / Q000276:immunology*; D005092:Exonucleases / Q000096:biosynthesis / Q000276:immunology; D005095:Exoribonucleases; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins / Q000276:immunology* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000276:immunology*; D053586:Virus Internalization; D014779:Virus Replication / Q000276:immunology; D014902:West Nile virus / Q000276:immunology*; D019892:eIF-2 Kinase / Q000096:biosynthesis / Q000276:immunology; D000090123:Viperin Protein
D005092:Exonucleases; D005095:Exoribonucleases; D016898:Interferon-alpha; D008565:Membrane Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; D016601:RNA-Binding Proteins; D019892:eIF-2 Kinase; C080081:IFITM2 protein, human; C080082:IFITM3 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein; C112346:ISG20 protein, human