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Journal of Virology, November 2006, p. 11370-11380, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01041-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Phospholipase A2 Activity-Dependent Stimulation of Ca2+ Entry by Human Parvovirus B19 Capsid Protein VP1{triangledown}

Adrian Lupescu,1,{dagger} C.-Thomas Bock,2,{dagger} Philipp A. Lang,1,2 Susanne Aberle,2 Heike Kaiser,2 Reinhard Kandolf,2 and Florian Lang1*

Departments of Physiology,1 Molecular Pathology, University of Tübingen, Tübingen, Germany2

Received 22 May 2006/ Accepted 28 August 2006

Recent reports demonstrated an association of human parvovirus B19 with inflammatory cardiomyopathy (iCMP), which is accompanied by endothelial dysfunction. As intracellular Ca2+ activity is a key regulator of cell function and participates in mechanisms leading to endothelial dysfunction, the present experiments explored the effects of the B19 capsid proteins VP1 and VP2. A secreted phospholipase A2 (PLA2)-like activity has been located in the VP1 unique region of the B19 minor capsid protein. As PLA2 has recently been shown to activate the store-operated or capacitative Ca2+ channel ICRAC, we analyzed the impact of the viral PLA2 motif on Ca2+ entry. We cloned the VP1 and VP2 genes isolated from a patient suffering from fatal B19 iCMP into eukaryotic expression vectors. We also generated a B19 replication-competent plasmid to demonstrate PLA2 activity under the control of the complete B19 genome. After the transfection of human endothelial cells (HMEC-1), cytosolic Ca2+ activity was determined by utilizing Fura-2 fluorescence. VP1 and VP2 expression did not significantly modify basal cytosolic Ca2+ activity or the decline of cytosolic Ca2+ activity following the removal of extracellular Ca2+. However, expression of VP1 and of the full-length B19 clone, but not of VP2, significantly accelerated the increase of cytosolic Ca2+ activity following the readdition of extracellular Ca2+ in the presence of thapsigargin, indicating an activation of ICRAC. The effect of VP1 was mimicked by the PLA2 product lysophosphatidylcholine and abolished by an inactivating mutation of the PLA2-encoding region of the VP1 gene. Our observations point to the activation of Ca2+ entry by VP1 PLA2 activity, an effect likely participating in the pathophysiology of B19 infection.

* Corresponding author. Mailing address: Physiologisches Institut, der Universität Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany. Phone: 49 7071 29 72194. Fax: 49 7071 29 5618. E-mail: florian.lang{at}uni-tuebingen.de.

{triangledown} Published ahead of print on 6 September 2006.

{dagger} A.L. and C.T.B. contributed equally to this study and thus share first authorship.

Journal of Virology, November 2006, p. 11370-11380, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01041-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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