CD147 Promotes Entry of Pentamer-Expressing Human Cytomegalovirus into Epithelial and Endothelial Cells

Abstract

Human cytomegalovirus (HCMV) replicates in many diverse cell types in vivo, and entry into different cells involves distinct entry mechanisms and different envelope glycoproteins. HCMV glycoprotein gB is thought to act as the virus fusogen, apparently after being triggered by different gH/gL proteins that bind distinct cellular receptors or entry mediators. A trimer of gH/gL/gO is required for entry into all cell types, and entry into fibroblasts involves trimer binding to platelet-derived growth factor receptor alpha (PDGFRα). HCMV entry into biologically relevant epithelial and endothelial cells and monocyte-macrophages also requires a pentamer, gH/gL complexed with UL128, UL130, and UL131, and there is evidence that the pentamer binds unidentified receptors. We screened an epithelial cell cDNA library and identified the cell surface protein CD147, which increased entry of pentamer-expressing HCMV into HeLa cells but not entry of HCMV that lacked the pentamer. A panel of CD147-specific monoclonal antibodies inhibited HCMV entry into epithelial and endothelial cells, but not entry into fibroblasts. shRNA silencing of CD147 in endothelial cells inhibited HCMV entry but not entry into fibroblasts. CD147 colocalized with HCMV particles on cell surfaces and in endosomes. CD147 also promoted cell-cell fusion induced by expression of pentamer and gB in epithelial cells. However, soluble CD147 did not block HCMV entry and trimer and pentamer did not bind directly to CD147, supporting the hypothesis that CD147 acts indirectly through other proteins. CD147 represents the first HCMV entry mediator that specifically functions to promote entry of pentamer-expressing HCMV into epithelial and endothelial cells.

Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence

“…Intriguingly, all of these factors involved in the entry of SARS-CoV-2 in the host cell are known to be expressed by endothelial cells [43][44][45][46][47][48][49] (Figure 1).…”

Single-cell transcriptome analysis of CD34+stem cell-derived myeloid cells identifies a CFU-GEMM-like population permissive to human cytomegalovirus infection

“…The extent of expression of genes encoding potential CMV entry receptors, such as EGFR [25–28], PDGFRA [29–31], THY1/CD90 [32, 33], the integrins αVβ3, α2β1, and α6β1 [34–36], and BSG [37] was also queried. EGFR, THY1/CD90, and integrins β3, α2, and α6 were either not expressed at all or were found in less than ten cells, while PDGFRA was expressed in only 356 cells, and then only at low levels.…”

“…However, the fact that no “universal” entry resistance/enabling gene(s), expressed by all viral transcript +/− cells, could be identified implies that such gene(s) may not exist. This is in contrast to other cell types such as endothelial and epithelial cells, whose infection instead depends on the expression of surface molecules (such as BSG), acting as receptors for specific glycoprotein complexes present on the virion’s surface [37].…”

Virus-Like Particles and Nanoparticles for Vaccine Development against HCMV

“…It is now accepted that the two main host cell receptors for HCMV involve the platelet-derived growth factor receptor α (PDGFRα) [66][67][68] and Neuropilin 2 (Nrp2) [55]. In addition, other cellular host factors were described as facilitators of viral entry such as the olfactory receptor family member OR14I1 [69], the adipocyte plasma membrane-associated protein (APMAP) [70], CD46 [71], and CD147 [72]. However, the biological relevance of this multitude of receptors remains to be understood.…”