The Influenza Virus Protein PB1-F2 Inhibits the Induction of Type I Interferon at the Level of the MAVS Adaptor Protein

PLoS Pathogens

Peter Palese¹  Rong Hai²  Mirco Schmolke²  Zsuzsanna T. Varga²  Irene Ramos²  Adolfo García-Sastre²  Ana Fernandez-Sesma³ 

[1] Department of Medicine, Mount Sinai School of Medicine, New York City, New York, United States of America;Department of Microbiology, Mount Sinai School of Medicine, New York City, New York, United States of America;Institute of Global Health and Emerging Pathogens, Mount Sinai School of Medicine, New York City, New York, United States of America

关键词: Interferons;    Influenza viruses;    293T cells;    Newcastle disease virus;    Dendritic cells;    Viral gene expression;    Protein expression;    Transfection;   

DOI  :  10.1371/journal.ppat.1002067

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

PB1-F2 is a 90 amino acid protein that is expressed from the +1 open reading frame in the PB1 gene of some influenza A viruses and has been shown to contribute to viral pathogenicity. Notably, a serine at position 66 (66S) in PB1-F2 is known to increase virulence compared to an isogenic virus with an asparagine (66N) at this position. Recently, we found that an influenza virus expressing PB1-F2 N66S suppresses interferon (IFN)-stimulated genes in mice. To characterize this phenomenon, we employed several in vitro assays. Overexpression of the A/Puerto Rico/8/1934 (PR8) PB1-F2 protein in 293T cells decreased RIG-I mediated activation of an IFN-β reporter and secretion of IFN as determined by bioassay. Of note, the PB1-F2 N66S protein showed enhanced IFN antagonism activity compared to PB1-F2 wildtype. Similar observations were found in the context of viral infection with a PR8 PB1-F2 N66S virus. To understand the relationship between NS1, a previously described influenza virus protein involved in suppression of IFN synthesis, and PB1-F2, we investigated the induction of IFN when NS1 and PB1-F2 were co-expressed in an in vitro transfection system. In this assay we found that PB1-F2 N66S further reduced IFN induction in the presence of NS1. By inducing the IFN-β reporter at different levels in the signaling cascade, we found that PB1-F2 inhibited IFN production at the level of the mitochondrial antiviral signaling protein (MAVS). Furthermore, immunofluorescence studies revealed that PB1-F2 co-localizes with MAVS. In summary, we have characterized the anti-interferon function of PB1-F2 and we suggest that this activity contributes to the enhanced pathogenicity seen with PB1-F2 N66S- expressing influenza viruses.

【 授权许可】

CC BY