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Journal of Virology, July 2007, p. 7776-7785, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.00546-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Induction of MxA Gene Expression by Influenza A Virus Requires Type I or Type III Interferon Signaling

Dirk Holzinger,¹ Carl Jorns,¹ Silke Stertz,¹ Stéphanie Boisson-Dupuis,³ Robert Thimme,² Manfred Weidmann,^1, Jean-Laurent Casanova,³ Otto Haller,¹ and Georg Kochs^1*

Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene,¹ Abteilung für Innere Medizin II, Universitätsklinikum Freiburg, D-79008 Freiburg, Germany,² Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-INSERM U550, Necker-Enfants Malades Medical School, 75015 Paris, France³

Received 16 March 2006/ Accepted 13 April 2007

The human MxA gene belongs to the class of interferon (IFN)-stimulated genes (ISGs) involved in antiviral resistance against influenza viruses. Here, we studied the requirements for MxA induction by influenza A virus infection. MxA is transcriptionally upregulated by type I (alpha and beta) and type III (lambda) IFNs. Therefore, MxA is widely used in gene expression studies as a reliable marker for IFN bioactivity. It is not known, however, whether viruses can directly activate MxA expression in the absence of secreted IFN. By using an NS1-deficient influenza A virus and human cells with defects in IFN production or the STAT1 gene, we studied the induction profile of MxA by real-time reverse transcriptase PCR. The NS1-deficient virus is known to be a strong activator of the IFN system because NS1 acts as a viral IFN-antagonistic protein. Nevertheless, MxA gene expression was not inducible by this virus upon infection of IFN nonproducer cells and STAT1-null cells. Likewise, neither IFN- nor IFN- had a sizeable effect on the STAT1-null cells, indicating that MxA expression requires STAT1 signaling and cannot be triggered directly by virus infection. In contrast, the expression of the IFN-stimulated gene ISG56 was induced by influenza virus in these cells, confirming that ISG56 differs from MxA in being directly inducible by viral triggers in an IFN-independent way. In summary, our study reveals that MxA is a unique marker for the detection of type I and type III IFN activity during virus infections and IFN therapy.

Published ahead of print on 9 May 2007.

Present adress: Manfred Weidmann, Institut für Virologie, Universität Göttingen, D-37075 Göttingen, Germany.

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