Human cytomegalovirus (HCMV) is the leading cause of congenital infection, associated with severe birth defects and intrauterine growth retardation. The mechanism of HCMV transmission via the maternal-fetal interface is largely unknown, and there are no animal models for HCMV.
The initial stages of infection are believed to occur in the maternal decidua. Here we employed a novel decidual organ culture, using both clinically- and laboratory-derived viral strains, for the ex vivo modeling of HCMV transmission in the maternal-fetal interface.
Viral spread in the tissue was demonstrated by progression of infected-cell foci with a 2-log increase in HCMV DNA between 3-9 days post infection, expression of immediate-early and late proteins, appearance of typical histopathological features of natural infection, and a dose-dependent inhibition of infection by ganciclovir and acyclovir.
HCMV infected a wide-range of cells in the decidua, including invasive cytotrophoblasts, macrophages, endothelial, decidual, and dendritic cells. Cell-to-cell viral spread was revealed by focal extension of infected-cell clusters, inability to recover infectious extracellular virus, and high relative proportions (85-95%) of cell-associated viral DNA. Intriguingly, neutralizing HCMV hyperimmune globulins exhibited inhibitory activity on viral spread in the decidua even when added at 24 hrs post infection– providing a mechanistic basis for their clinical use in prenatal prevention.
The ex-vivo infected decidual cultures present a unique insight into patterns of viral tropism and spread, defining initial stages of congenital HCMV transmission, and can serve to evaluate the effect of new antiviral interventions within the maternal-fetal interface milieu.
Yiska Weisblum1,2, Amos Panet2, Zichria Zakay-Rones2, Ronit Haimov-Kochman3, Debra Goldman-Wohl3, Ilana Ariel4, Haya Falk2, Shira Natanson-Yaron3, Miri D. Goldberg1,2, Ronit Gilad3, Caryn Greenfield3, Simcha Yagel3, Dana G. Wolf1
1Clinical Virology Unit
2Department of Biochemistry and the Chanock center for Virology, IMRIC
3Department of Obstetrics and Gynecology
4Department of Pathology, Hadassah Hebrew University Medical Center & Faculty of Medicine, Jerusalem, Israel