Direct infection of primary endothelial cells with human cytomegalovirus prevents angiogenesis and migration

Research output: Contribution to journalArticle

Authors

  • Rasmus K L Gustafsson
  • Koon-Chu Yaiw
  • Vanessa Wilhelmi
  • Ourania N Kostopoulou
  • Belghis Davoudi
  • Afsar Rahbar
  • Melinda Benard
  • Thomas Renné
  • Cecilia Söderberg-Nauclér
  • Lynn M Butler

Abstract

Human cytomegalovirus (hCMV) is a beta herpesvirus that establishes lifelong infection. Although the virus does not usually cause overt clinical symptoms in immunocompetent individuals it can have deleterious effects in immunocompromised patients, such as those on post-transplant medication or with HIV infection. hCMV is the most common congenital infection and can lead to serious fetal sequelae. Endothelial cells (ECs) are natural hosts for hCMV in vivo, therefore, investigations of how this cell type is modulated by infection are key to understanding hCMV pathogenesis. Previous studies have examined the effect of secretomes from hCMV-infected cells on EC angiogenesis, whereas the effect of direct infection on this process has not been so well investigated. Here, we show that placental ECs are viral targets during congenital infection and that vessels in infected tissue appear morphologically abnormal. We demonstrate that the clinical hCMV strain VR1814 impaired EC tube assembly in in vitro angiogenesis assays and inhibited wound healing ability in scratch assays. Secretomes from infected cultures did not impair angiogenesis of uninfected ECs, suggesting that cell-intrinsic changes, as opposed to secreted factors, were responsible. We observed viral gene transcription dependent downregulation of the expression of angiogenesis-associated genes, including angiopoietin-2, TEK receptor and vascular endothelial growth factor receptors. An alternative clinical hCMV stain, TB40E showed similar effects on EC angiogenesis. Together, our data indicate that direct infection with hCMV can induce an anti-migratory and anti-angiogenic EC phenotype, which could have a detrimental effect on the vasculature development in infected tissues.

Details

Original languageEnglish
Pages (from-to)3598-3612
Number of pages15
JournalJournal of General Virology
Volume96
Issue number12
Publication statusPublished - Dec 2015

Keywords

  • Cell Movement, Cells, Cultured, Cytomegalovirus, Cytomegalovirus Infections, Endothelial Cells, Female, Gene Expression Regulation, Viral, Humans, Infectious Disease Transmission, Vertical, Interleukin-10, Neovascularization, Physiologic, Placenta, Pregnancy, RNA, Messenger