Evidence for a Novel Mechanism of Influenza Virus-Induced Type I Interferon Expression by a Defective RNA-Encoded Protein

PLoS Pathogens

Thorsten Wolff¹  Stephan Ludwig²  Jürgen Brosius³  Gerrit Randau³  Timofey S. Rozhdestvensky³  Thomas Robeck³  Mirco Schmolke⁴  Yvonne Boergeling⁴  Patricia Resa-Infante⁵  Gülsah Gabriel⁵ 

[1] Division of Influenza Viruses and Other Respiratory Viruses, Robert Koch Institute, Berlin, Germany;Institute of Evolutionary and Medical Genomics, Brandenburg Medical School (MHB), Neuruppin, Germany;Institute of Experimental Pathology, Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany;Institute of Molecular Virology (IMV), Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany;Viral Zoonosis and Adaptation, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany

关键词: Influenza A virus;    Viral replication;    RNA interference;    RNA viruses;    Polymerases;    H5N1;    Small interfering RNAs;    Interferons;   

DOI  :  10.1371/journal.ppat.1004924

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Influenza A virus (IAV) defective RNAs are generated as byproducts of error-prone viral RNA replication. They are commonly derived from the larger segments of the viral genome and harbor deletions of various sizes resulting in the generation of replication incompatible viral particles. Furthermore, small subgenomic RNAs are known to be strong inducers of pattern recognition receptor RIG-I-dependent type I interferon (IFN) responses. The present study identifies a novel IAV-induced defective RNA derived from the PB2 segment of A/Thailand/1(KAN-1)/2004 (H5N1). It encodes a 10 kDa protein (PB2∆) sharing the N-terminal amino acid sequence of the parental PB2 protein followed by frame shift after internal deletion. PB2∆ induces the expression of IFNβ and IFN-stimulated genes by direct interaction with the cellular adapter protein MAVS, thereby reducing viral replication of IFN-sensitive viruses such as IAV or vesicular stomatitis virus. This induction of IFN is completely independent of the defective RNA itself that usually serves as pathogen-associated pattern and thus does not require the cytoplasmic sensor RIG-I. These data suggest that not only defective RNAs, but also some defective RNA-encoded proteins can act immunostimulatory. In this particular case, the KAN-1-induced defective RNA-encoded protein PB2∆ enhances the overwhelming immune response characteristic for highly pathogenic H5N1 viruses, leading to a more severe phenotype in vivo.

【 授权许可】

CC BY