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Journal of Virology, August 2008, p. 7942-7952, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00891-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Parvovirus B19 NS1 Protein Modulates Inflammatory Signaling by Activation of STAT3/PIAS3 in Human Endothelial Cells{triangledown}

Anja Duechting,1 Carsten Tschöpe,2 Heike Kaiser,1 Tobias Lamkemeyer,3 Nobuyuki Tanaka,4 Susanne Aberle,1 Florian Lang,5 Joseph Torresi,6 Reinhard Kandolf,1 and C.-Thomas Bock1*

Department of Molecular Pathology, Institute for Pathology, University Hospital of Tuebingen, Tuebingen, Germany,1 Department of Cardiology and Pneumology, Charité-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany,2 Proteom Centrum Tuebingen, University of Tuebingen, Tuebingen, Germany,3 Department of Cancer Science, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan,4 Institute of Physiology, University of Tuebingen, Tuebingen, Germany,5 Department of Medicine, Victorian Infectious Diseases Service, Royal Melbourne Hospital, Victoria, Australia6

Received 29 April 2008/ Accepted 4 June 2008

The pathogenic mechanism by which parvovirus B19 may induce inflammatory cardiomyopathy (iCMP) is complex but is known to involve inflammatory processes, possibly including activation of JAK/STAT signaling. The nonstructural B19 protein NS1 acts as a transactivator triggering signaling cascades that eventually lead to activation of interleukin 6 (IL-6). We examined the impact of NS1 on modulation of STAT signaling in human endothelial cells (HMEC-1). The NS1 sequences were identified from B19 DNA isolated from the myocardia of patients with fatal iCMP. B19 infection as well as NS1 overexpression in HMEC-1 cells produced a significant upregulation in the phosphorylation of both tyrosine705 and serine727 STAT3 (P < 0.05). The increased STAT3 phosphorylation was accompanied by dimerization, nuclear translocation, and DNA binding of pSTAT3. In contrast, NS1 expression did not result in increased STAT1 activation. Notably, the expression levels of the negative regulators of STAT activation, SOCS1 and SOCS3, were not altered by NS1. However, the level of PIAS3 was upregulated in NS1-expressing HMEC-1 cells. Analysis of the transcriptional activation of target genes revealed that NS1-induced STAT3 signaling was associated with upregulation of genes involved in immune response (e.g., the IFNAR1 and IL-2 genes) and downregulation of genes associated with viral defense (e.g., the OAS1 and TYK2 genes). Our results demonstrate that B19 NS1 modulates the STAT/PIAS pathway. The NS1-induced upregulation of STAT3/PIAS3 in the absence of STAT1 phosphorylation and the lack of SOCS1/SOCS3 activation may contribute to the mechanisms by which B19 evades the immune response and establishes persistent infection in human endothelial cells. Thus, NS1 may play a critical role in the mechanism of viral pathogenesis in B19-associated iCMP.

* Corresponding author. Mailing address: Department of Molecular Pathology, Institute for Pathology, University of Tuebingen, 72076 Tuebingen, Germany. Phone: 49 7071 29 86889. Fax: 49 7071 29 5334. E-mail: thomas.bock{at}med.uni-tuebingen.de

{triangledown} Published ahead of print on 11 June 2008.

Journal of Virology, August 2008, p. 7942-7952, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00891-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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