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Platelet-derived growth factor-α receptor is the cellular receptor for human cytomegalovirus gHgLgO trimer

Nature Microbiology volume 1, Article number: 16082 (2016) Cite this article

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An Erratum to this article was published on 20 June 2016

Abstract

Human cytomegalovirus encodes at least 25 membrane glycoproteins that are found in the viral envelope1. While gB represents the fusion protein, two glycoprotein complexes control the tropism of the virus: the gHgLgO trimer is involved in the infection of fibroblasts, and the gHgLpUL128L pentamer is required for infection of endothelial, epithelial and myeloid cells2–5. Two reports suggested that gB binds to ErbB1 and PDGFRα (refs 6,7); however, these results do not explain the tropism of the virus and were recently challenged8,9. Here, we provide a 19 Å reconstruction for the gHgLgO trimer and show that it binds with high affinity through the gO subunit to PDGFRα, which is expressed on fibroblasts but not on epithelial cells. We also provide evidence that the trimer is essential for viral entry in both fibroblasts and epithelial cells. Furthermore, we identify the pentamer, which is essential for infection of epithelial cells, as a trigger for the ErbB pathway. These findings help explain the broad tropism of human cytomegalovirus and indicate that PDGFRα and the viral gO subunit could be targeted by novel anti-viral therapies.

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Figure 1: Evidence that trimer–PDGFR and pentamer–ErbB interactions determine cellular tropism for fibroblasts or epithelial cells.
Figure 2: HCMV trimer is required for both fibroblast and epithelial cell infection, while HCMV pentamer is required for epithelial cells only.
Figure 3: The gHgLgO trimer, but not the gHgL dimer, binds with high affinity to PDGFRα.
Figure 4: Visualization of the gHgLgO–PDGFRα complex.

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Acknowledgements

The authors thank A. von Heyl for graphical representation, the Virologia e Microbiologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, for the HCMV clinical isolate and deficient virus, Horizon Genomics GmbH for the HAP-1 parental line and CRISPR/Cas9 KO cells and Oxford University, Central Proteomics Facility, Oxford, UK, for mass spectrometry analysis. The Institute for Research in Biomedicine is supported by the Helmut Horten Foundation. This project has been funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract no. HHSN261200800001E, and by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Leidos Biomedical Research provided support in the form of a salary for author Y.T.

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Author notes

  1. Anna Kabanova

    Present address: †Present address: Department of Life Sciences, University of Siena, via Aldo Moro 2, 53100 Siena, Italy,

  2. Anna Kabanova, Jessica Marcandalli and Tongqing Zhou: These authors contributed equally to this work.

  3. Antonio Lanzavecchia and Laurent Perez: These authors jointly supervised this work.

Authors and Affiliations

  1. Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland

    Anna Kabanova, Jessica Marcandalli, Chiara Silacci-Fregni, Mathilde Foglierini, Blanca Maria Fernandez-Rodriguez, Roger Geiger, Federica Sallusto, Antonio Lanzavecchia & Laurent Perez

  2. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Tongqing Zhou, Aliaksandr Druz, Baoshan Zhang & Peter D. Kwong

  3. Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland

    Siro Bianchi & Davide Corti

  4. Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, 21702, Maryland, USA

    Ulrich Baxa & Yaroslav Tsybovsky

  5. Laboratori Sperimentali di Ricerca-Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy

    Daniele Lilleri

  6. Institute for Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland

    Roger Geiger & Antonio Lanzavecchia

  7. Istituto Nazionale Genetica Molecolare ‘Romeo ed Enrica Invernizzi’, 20122 Milano, Italy

    Massimiliano Pagani

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Contributions

A.K., J.M., S.B., D.L. and R.G. performed and analysed the experiments. C.S.-F. and B.M.F.-R. generated new reagents. B.M.F.-R., M.F. and M.P. performed and provided analysis on the gene expression of ARPE-19 and MRC-9 cells. T.Z., U.B., Y.T., A.D., B.Z. and P.D.K. designed, performed and analysed electron microscopy data and expressed and purified the PDGFRα-trimer complex. F.S. provided intellectual input and wrote the manuscript. D.C. designed experiments, analysed the data and wrote the manuscript. A.L. designed experiments, analysed the data, wrote the manuscript and provided supervision. L.P. designed experiments, analysed the data, provided supervision and wrote the manuscript.

Corresponding authors

Correspondence to Antonio Lanzavecchia or Laurent Perez.

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The authors declare no competing financial interests.

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Kabanova, A., Marcandalli, J., Zhou, T. et al. Platelet-derived growth factor-α receptor is the cellular receptor for human cytomegalovirus gHgLgO trimer. Nat Microbiol 1, 16082 (2016). https://doi.org/10.1038/nmicrobiol.2016.82

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