The Ebola Virus VP35 Protein Functions as a Type I IFN Antagonist

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 22; pp. 12289 - 12294
• Main Authors: Basler, Christopher F., Wang, Xiuyan, Muhlberger, Elke, Volchkov, Victor, Paragas, Jason, Klenk, Hans-Dieter, Garcia-Sastre, Adolfo, Palese, Peter
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 24.10.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Antivirals; Biological Sciences; Cell Line; Cells; Dogs; Double stranded RNA; Ebola virus; Humans; Infections; Influenza A virus; Influenza A virus - genetics; Influenza A virus - growth & development; Influenza A virus - physiology; Interferon Type I - antagonists & inhibitors; Microbiology; NS1 protein; Nucleocapsid Proteins; Nucleoproteins - physiology; Plasmids; Promoter Regions, Genetic; Proteins; Ribosomes - genetics; Sendai virus; Viral Core Proteins - physiology; Viral Nonstructural Proteins - genetics; Virology; Virus Replication; Viruses; VP35 protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.220398297

An assay has been developed that allows the identification of molecules that function as type I IFN antagonists. Using this assay, we have identified an Ebola virus-encoded inhibitor of the type I IFN response, the Ebola virus VP35 protein. The assay relies on the properties of an influenza virus mutant, influenza delNS1 virus, which lacks the NS1 ORF and, therefore, does not produce the NS1 protein. When cells are infected with influenza delNS1 virus, large amounts of type I IFN are produced. As a consequence, influenza delNS1 virus replicates poorly. However, high-efficiency transient transfection of a plasmid encoding a protein that interferes with type I IFN-induced antiviral functions, such as the influenza A virus NS1 protein or the herpes simplex virus protein ICP34.5, rescues growth of influenza delNS1 virus. When plasmids expressing individual Ebola virus proteins were transfected into Madin Darby canine kidney cells, the Ebola virus VP35 protein enhanced influenza delNS1 virus growth more than 100-fold. VP35 subsequently was shown to block double-stranded RNA- and virus-mediated induction of an IFN-stimulated response element reporter gene and to block double-stranded RNA- and virus-mediated induction of the IFN-β promoter. The Ebola virus VP35 therefore is likely to inhibit induction of type I IFN in Ebola virus-infected cells and may be an important determinant of Ebola virus virulence in vivo.