Induction of MxA gene expression by influenza A virus requires type I or type III interferon signaling.
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-alpha nor IFN-lambda 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.
Holzinger
Dirk
D
Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Hermann-Herder-Strasse 11, D-79104 Freiburg, Germany.
Jorns
Carl
C
Stertz
Silke
S
Boisson-Dupuis
Stéphanie
S
Thimme
Robert
R
Weidmann
Manfred
M
Casanova
Jean-Laurent
JL
Haller
Otto
O
Kochs
Georg
G
D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D019204:GTP-Binding Proteins / Q000235:genetics*; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D016898:Interferon-alpha / Q000096:biosynthesis / Q000378:metabolism*; D064547:Myxovirus Resistance Proteins; D011401:Promoter Regions, Genetic; D015398:Signal Transduction
D017931:DNA Primers; D016898:Interferon-alpha; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D019204:GTP-Binding Proteins