The PB2 Subunit of the Influenza Virus RNA Polymerase Affects Virulence

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[SIZE=-1]Journal of Virology, September 2010, p. 8433-8445, Vol. 84, No. 17
0022-538X/10/$012.00+0 doi:10.1128/JVI.00879-10
Copyright ? 2010, American Society for Microbiology. All Rights Reserved.[/SIZE]

The PB2 Subunit of the Influenza Virus RNA Polymerase Affects Virulence by Interacting with the Mitochondrial Antiviral Signaling Protein and Inhibiting Expression of Beta Interferon<sup>

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Katy M. Graef,¹^,2<sup>,

</sup> Frank T. Vreede,² Yuk-Fai Lau,¹^,3 Amber W. McCall,¹ Simon M. Carr,²<sup>,

</sup> Kanta Subbarao,¹^* and Ervin Fodor²^* Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,¹ Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom,² Medical Countermeasures (Biological) Laboratory, DMERI, DSO National Laboratories, Singapore 117510³
Received 23 April 2010/ Accepted 5 June 2010
<!-- ABS --> The PB2 subunit of the influenza virus RNA polymerase is a majorvirulence determinant of influenza viruses. However, the molecularmechanisms involved remain unknown. It was previously shownthat the PB2 protein, in addition to its nuclear localization,also accumulates in the mitochondria. Here, we demonstrate thatthe PB2 protein interacts with the mitochondrial antiviral signalingprotein, MAVS (also known as IPS-1, VISA, or Cardif), and inhibitsMAVS-mediated beta interferon (IFN-β) expression. In addition,we show that PB2 proteins of influenza viruses differ in theirabilities to associate with the mitochondria. In particular,the PB2 proteins of seasonal human influenza viruses localizeto the mitochondria while PB2 proteins of avian influenza virusesare nonmitochondrial. This difference in localization is causedby a single amino acid polymorphism in the PB2 mitochondrialtargeting signal. In order to address the functional significanceof the mitochondrial localization of the PB2 protein in vivo,we have generated two recombinant human influenza viruses encodingeither mitochondrial or nonmitochondrial PB2 proteins. We foundthat the difference in the mitochondrial localization of thePB2 proteins does not affect the growth of these viruses incell culture. However, the virus encoding the nonmitochondrialPB2 protein induces higher levels of IFN-β and, in an animalmodel, is attenuated compared to the isogenic virus encodinga mitochondrial PB2. Overall this study implicates the PB2 proteinin the regulation of host antiviral innate immune pathways andsuggests an important role for the mitochondrial associationof the PB2 protein in determining virulence.