期刊
JOURNAL OF INFECTIOUS DISEASES
卷 209, 期 11, 页码 1744-1753出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jit829
关键词
Viral disease; interferon; signal transducers and activators of transcription; immune evasion; interferon antagonist; lyssavirus; rabies virus; Duvenhage virus; pathogenicity; replication
资金
- National Health and Medical Research Council Australia [1003244]
- Senior Principal Research Fellowship [1002486]
- Australian Research Council [DP110101749]
- European Union Seventh Framework Programme [278433]
- Ministry of Education, Culture, Sports, Science and Technology, Japan [23380179, 24580424]
- Grants-in-Aid for Scientific Research [24580424, 23380179] Funding Source: KAKEN
Background. Rabies virus (RABV) causes rabies disease resulting in >55 000 human deaths/year. The multifunctional RABV P-protein has essential roles in genome replication, and forms interactions with cellular STAT proteins that are thought to underlie viral antagonism of interferon-dependent immunity. However, the molecular details of P-protein-STAT interaction, and its importance to disease are unresolved. Methods.aEuro integral Studies were performed using sequence/structure analysis, mutagenesis, immunoprecipitation, luciferase and qRT-PCR-based signaling assays, confocal microscopy and reverse genetics/in vivo infection. Results.aEuro integral We identified a hydrophobic pocket of the P-protein C-terminal domain as critical to STAT-binding/antagonism. This interface was found to be functionally and spatially independent of the region responsible for N-protein interaction, which is critical to genome replication. Based on these findings, we generated the first mutant RABV lacking STAT-association. Growth of the virus in vitro was unimpaired, but it lacked STAT-antagonist function and was highly sensitive to interferon. Importantly, growth of the virus was strongly attenuated in brains of infected mice, producing no major neurological symptoms, compared with the invariably lethal wild-type virus. Conclusions.aEuro integral These data represent direct evidence that P-protein-STAT interaction is critical to rabies, and provide novel insights into the mechanism by which RABV coordinates distinct functions in interferon antagonism and replication.
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