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PLoS Pathog. 2015 May 29;11(5):e1004924. doi: 10.1371/journal.ppat.1004924. eCollection 2015 May.

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

Author information

1
Institute of Molecular Virology (IMV), Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany.
2
Institute of Experimental Pathology, Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany.
3
Viral Zoonosis and Adaptation, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
4
Division of Influenza Viruses and Other Respiratory Viruses, Robert Koch Institute, Berlin, Germany.
5
Institute of Experimental Pathology, Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany; Institute of Evolutionary and Medical Genomics, Brandenburg Medical School (MHB), Neuruppin, Germany.
6
Institute of Molecular Virology (IMV), Center for Molecular Biology of Inflammation (ZMBE), University of Muenster, Muenster, Germany; Interdisciplinary Center of Clinical Research (IZKF), Medical Faculty, University of Muenster, Muenster, Germany; Cells-in-Motion Cluster of Excellence, University of Muenster, Muenster, Germany.

Abstract

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.

PMID:
26024522
PMCID:
PMC4449196
DOI:
10.1371/journal.ppat.1004924
[Indexed for MEDLINE]
Free PMC Article

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