Inhibition of human cytomegalovirus entry into mucosal epithelial cells

• Published in: Antiviral research Vol. 230; p. 105971
• Main Authors: He, Li, Hertel, Laura, James, Claire D., Morgan, Iain M., Klingelhutz, Aloysius J., Fu, Tong-Ming, Kauvar, Lawrence M., McVoy, Michael A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-10-2024
• Subjects: Cytomegalovirus; Entry mechanisms; Glycoproteins; Mucosal epithelial cells; Neutralizing antibodies; Cytomegalovirus; Mucosal epithelial cells; Glycoproteins; Neutralizing antibodies; Entry mechanisms; entry mechanisms; neutralizing antibodies; glycoproteins; cytomegalovirus; mucosal epithelial cells
• ISSN: 0166-3542; 1872-9096; 1872-9096
• DOI: 10.1016/j.antiviral.2024.105971

Human cytomegalovirus (CMV) causes serious developmental disabilities in newborns infected in utero following oral acquisition by the mother. Thus, neutralizing antibodies in maternal saliva have potential to prevent maternal infection and, consequently, fetal transmission and disease. Based on standard cell culture models, CMV entry mediators (and hence neutralizing targets) are cell type-dependent: entry into fibroblasts requires glycoprotein B (gB) and a trimeric complex (TC) of glycoproteins H, L, and O, whereas endothelial and epithelial cell entry additionally requires a pentameric complex (PC) of glycoproteins H and L with UL128, UL130, and UL131A. However, as the mediators of mucosal cell entry and the potential impact of cellular differentiation remained unclear, the present studies utilized mutant viruses, neutralizing antibodies, and soluble TC-receptor to determine the entry mediators required for infection of mucocutaneus cell lines and primary tonsil epithelial cells. Entry into undifferentiated cells was largely PC-dependent, but PC-independent entry could be induced by differentiation. TC-independent entry was also observed and varied by cell line and differentiation. Infection of primary tonsil cells from some donors was entirely TC-independent. In contrast, an antibody to gB or disruption of virion attachment using heparin blocked entry into all cells. These findings indicate that CMV entry into the spectrum of cell types encountered in vivo is likely to be more complex than has been suggested by standard cell culture models and may be influenced by the relative abundance of virion envelope glycoprotein complexes as well as by cell type, tissue of origin, and state of differentiation.
•Mucocutaneous cells do not fully adhere to the paradigms established by standard cell culture models.•CMV entry into cells encountered in vivo is more complex than has been suggested by standard cell culture models.•These findings are important for development of vaccines, immunotherapeutics, or other inhibitors that target virion entry.