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Adherens junction protein nectin-4 is the epithelial receptor for measles virus

Nature volume 480, pages 530–533 (2011)Cite this article

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Abstract

Measles virus is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths1,2. Although it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to infect initially macrophages and dendritic cells of the airways using signalling lymphocytic activation molecule family member 1 (SLAMF1; also called CD150) as a receptor3,4,5,6. These cells then cross the respiratory epithelium and transport the infection to lymphatic organs where measles virus replicates vigorously7. How and where the virus crosses back into the airways has remained unknown. On the basis of functional analyses of surface proteins preferentially expressed on virus-permissive human epithelial cell lines, here we identify nectin-4 (ref. 8; also called poliovirus-receptor-like-4 (PVRL4)) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains measles virus entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is downregulated in infected epithelial cells, including those of macaque tracheae. Although other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that measles virus targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer9,10,11, which has implications for ongoing measles-virus-based clinical trials of oncolysis12.

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Figure 1: Identification of nectin-4 as a candidate measles virus receptor.
Figure 2: V domain of nectin-4 supports strong binding to measles virus H protein.
Figure 3: Nectin-4 is necessary for measles virus infection of well-differentiated human airway epithelia.
Figure 4: Nectin-4 expression and infection of monkey tracheal epithelium.

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Acknowledgements

We thank J. Brüning, A. Schnoor Cancio, A. Peterson, I. Meunier and C. Thibault for technical assistance; Y. Yanagi for Vero-hSLAM cells and p(+)MV323-EGFP; T. Stehle for soluble SLAMF1; J. Fournier and G. Kobinger for facilitating the macaque studies; and R. König, D. Schilling-Leiß and T. Miest for discussions. This paper is dedicated to Heinz Schaller by one of his students. This work was supported by grants BMG 2510-FSB-705 to M.D.M.; NIH R01 AI063476 and NIH R01 CA090636 to R.C.; the Roy J. Carver Charitable Trust, Cell Culture Core and Cell Morphology Cores, partially supported by the Center for Gene Therapy for Cystic Fibrosis (NIH P30 DK-54759), and the Cystic Fibrosis Foundation to P.B.M.; and CIHR MOP-66989 and CFI 9488 to V.v.M.; INSERM, Institut Paoli-Calmettes and the Ligue Nationale Contre le Cancer (label 2009–11) to M.L. X.X.W. was supported by a CIHR Master’s Award.

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Authors and Affiliations

  1. Division of Medical Biotechnology, Paul-Ehrlich-Institut, 63225 Langen, Germany,

    Michael D. Mühlebach, Steffen Prüfer, Katharina M. Uhlig & Klaus Cichutek

  2. Department of Molecular Medicine, Mayo Clinic, Rochester, 55902, Minnesota, USA

    Mathieu Mateo, Vincent H. J. Leonard, Chanakha K. Navaratnarajah, Marie Frenzke & Roberto Cattaneo

  3. Department of Pediatrics University of Iowa Carver College of Medicine, Iowa City, 52242, Iowa, USA

    Patrick L. Sinn, Shyam Ramachandran & Paul B. McCray

  4. INRS and Institut Armand Frappier, University of Quebec, Laval, Quebec H7V 1B7, Canada,

    Xiao X. Wong, Bevan Sawatsky & Veronika von Messling

  5. Duke University and National University of Singapore, 169857 Singapore, Singapore,

    Veronika von Messling

  6. INSERM, UMR891/CRCM and University of Aix-Marseille, 13009 Marseille, France,

    Marc Lopez

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  1. Michael D. Mühlebach
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Contributions

V.H.J.L. and M.D.M. conceived the project with R.C., who coordinated research. V.H.J.L., S.P., K.M.U. and M.D.M. performed and evaluated screens, and validated nectin-4 as candidate receptor. M.L. contributed purified proteins, antibodies and cell lines, and advised about their use. M.M. and C.K.N. characterized nectin-4 function biochemically and in cells. P.L.S., S.R. and P.B.M. planned and executed experiments with well-differentiated human epithelial sheets. M.F., X.X.W., B.S. and V.v.M. planned and executed monkey infection experiments and their analyses. R.C., M.M. and M.D.M. wrote the paper; V.v.M., K.C., P.B.M. and M.L. edited the paper.

Corresponding author

Correspondence to Roberto Cattaneo.

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The authors declare no competing financial interests.

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Mühlebach, M., Mateo, M., Sinn, P. et al. Adherens junction protein nectin-4 is the epithelial receptor for measles virus. Nature 480, 530–533 (2011). https://doi.org/10.1038/nature10639

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