Excessive production and extreme editing of human metapneumovirus defective interfering RNA is associated with type I IFN induction.
Type I IFN production is one of the hallmarks of host innate immune responses upon virus infection. Whilst most respiratory viruses carry IFN antagonists, reports on human metapneumovirus (HMPV) have been conflicting. Using deep sequencing, we have demonstrated that HMPV particles accumulate excessive amounts of defective interfering RNA (DIs) rapidly upon in vitro passage, and that these are associated with IFN induction. Importantly, the DIs were edited extensively; up to 70% of the original A and T residues had mutated to G or C, respectively. Such high editing rates of viral RNA have not, to our knowledge, been reported before. Bioinformatics and PCR assays indicated that adenosine deaminase acting on RNA (ADAR) was the most likely editing enzyme. HMPV thus has an unusually high propensity to generate DIs, which are edited at an unprecedented high frequency. The conflicting published data on HMPV IFN induction and antagonism are probably explained by DIs in virus stocks. The interaction of HMPV DIs with the RNA-editing machinery and IFN responses warrants further investigation.
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Bernadette G
BG
van den Hoogen
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Sander
S
van Boheemen
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Jonneke
J
de Rijck
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Stefan
S
van Nieuwkoop
Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, UK.
Derek J
DJ
Smith
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Brigitta
B
Laksono
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Alexander
A
Gultyaev
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Albert D M E
ADME
Osterhaus
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Ron A M
RAM
Fouchier
D000243:Adenosine Deaminase; D000818:Animals; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D029121:Metapneumovirus / Q000235:genetics* / Q000276:immunology*; D008969:Molecular Sequence Data; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins
D007370:Interferon Type I; D034741:RNA, Small Interfering; D012367:RNA, Viral; D016601:RNA-Binding Proteins; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase