Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus

Abstract

Human cytomegalovirus (HCMV) is a widespread opportunistic herpesvirus that causes severe and fatal diseases in immune-compromised individuals, including organ transplant recipients and individuals with AIDS1. It is also a leading cause of virus-associated birth defects and is associated with atherosclerosis and coronary restenosis1,2,3. HCMV initiates infection and intracellular signalling by binding to its cognate cellular receptors4,5 and by activating several signalling pathways including those mediated by mitogen-activated protein kinase5,6,7, phosphatidylinositol-3-OH kinase8, interferons5,9, and G proteins10. But a cellular receptor responsible for viral entry and HCMV-induced signalling has yet to be identified. Here we show that HCMV infects cells by interacting with epidermal growth factor receptor (EGFR) and inducing signalling. Transfecting EGFR-negative cells with an EGFR complementary DNA renders non-susceptible cells susceptible to HCMV. Ligand displacement and crosslinking analyses show that HCMV interacts with EGFR through gB, its principal envelope glycoprotein. gB preferentially binds EGFR and EGFR–ErbB3 oligomeric molecules in Chinese hamster ovary cells transfected with erbB family cDNAs. Taken together, these data indicate that EGFR is a necessary component for HCMV-triggered signalling and viral entry.

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Figure 1: Activation of EGFR, PI(3)K and PLC-γ and Ca2+ mobilization by HCMV infection of human fibroblast HEL cells.
Figure 2: HCMV infection and activation of the PI(3)K kinase pathway require EGFR expression.
Figure 3: HCMV directly binds EGFR through gB.
Figure 4: As an EGFR ligand, gB induces receptor phosphorylation and viral gene expression in HCMV-infected CHO cells transfected with erbB1 (B1), erbB2 (B2), erbB3 (B3) and erbB4 (B4).

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Acknowledgements

We thank S. Kenney, D. Y. Huang, B. Y. Huang, D. Evers, A. Gartner, A. T. Pelletier and J. S. Pagano for discussion, technical assistance and critically reading the manuscript. This work was supported by grants from the National Institutes of Health (to E.-S. H.).

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Correspondence to Eng-Shang Huang.

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Wang, X., Huong, S., Chiu, M. et al. Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 424, 456–461 (2003). https://doi.org/10.1038/nature01818

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