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Journal of Virology, December 2006, p. 11539-11555, Vol. 80, No. 23
0022-538X/06/$08.00+0     doi:10.1128/JVI.01016-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Human Cytomegalovirus (HCMV) Infection of Endothelial Cells Promotes Naïve Monocyte Extravasation and Transfer of Productive Virus To Enhance Hematogenous Dissemination of HCMV{triangledown}

Gretchen L. Bentz,1 Marta Jarquin-Pardo,1 Gary Chan,1 M. Shane Smith,1 Christian Sinzger,2 and Andrew D. Yurochko1*

Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932,1 Institute for Medical Virology, University of Tübingen, 72076 Tübingen, Germany2

Received 17 May 2006/ Accepted 7 September 2006

Human cytomegalovirus (HCMV) pathogenesis is dependent on the hematogenous spread of the virus to host tissue. While data suggest that infected monocytes are required for viral dissemination from the blood to the host organs, infected endothelial cells are also thought to contribute to this key step in viral pathogenesis. We show here that HCMV infection of endothelial cells increased the recruitment and transendothelial migration of monocytes. Infection of endothelial cells promoted the increased surface expression of cell adhesion molecules (intercellular cell adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and platelet endothelial cell adhesion molecule 1), which were necessary for the recruitment of naïve monocytes to the apical surface of the endothelium and for the migration of these monocytes through the endothelial cell layer. As a mechanism to account for the increased monocyte migration, we showed that HCMV infection of endothelial cells increased the permeability of the endothelium. The cellular changes contributing to the increased permeability and increased naïve monocyte transendothelial migration include the disruption of actin stress fiber formation and the decreased expression of lateral junction proteins (occludin and vascular endothelial cadherin). Finally, we showed that the migrating monocytes were productively infected with the virus, documenting that the virus was transferred to the migrating monocyte during passage through the lateral junctions. Together, our results provide evidence for an active role of the infected endothelium in HCMV dissemination and pathogenesis.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, Louisiana 71130-3932. Phone: (318) 675-8332. Fax: (318) 675-5764. E-mail: ayuroc{at}lsuhsc.edu.

{triangledown} Published ahead of print on 20 September 2006.

Journal of Virology, December 2006, p. 11539-11555, Vol. 80, No. 23
0022-538X/06/$08.00+0     doi:10.1128/JVI.01016-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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