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.
Highlights
Influenza A viruses (IAV) belong to the family of Orthomyxoviridae and are characterized by a segmented single-stranded RNA genome with negative orientation
It has been shown that influenza A virus defective RNAs are generated upon passages in cell culture, and in infected humans, indicating that these subgenomic RNAs may be relevant in infections in vivo
We characterize a novel defective RNA derived from the PB2 segment of a highly pathogenic H5N1 influenza A virus
Summary
Influenza A viruses (IAV) belong to the family of Orthomyxoviridae and are characterized by a segmented single-stranded RNA genome with negative orientation. These eight segments encode nine structural and up to seven nonstructural proteins [1,2,3,4,5]. Non-infectious particles exhibiting an incomplete viral genome e.g. due to a large internal deletion within at least one segment, are defined as defective interfering particles (DIPs) [7, 8] These DIPs need the presence of a helper virus for replication of their defective RNA [9]. It has been shown that the competition for viral RNA polymerases and preferential packaging of over-abundant DI RNA segments interferes with replication and packaging of full-length segments of replication competent helper virus [7, 8, 11,12,13]
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