Measles virus targets adherens junction protein nectin-4 to emerge in the airways

Michael D. Mühlebach1, Mathieu Mateo2, Patrick L. Sinn3, Steffen Prüfer1, Katharina M. Uhlig1, Vincent H.J. Leonard2, Chanakha K. Navaratnarajah2, Marie Frenzke2, Xiao X. Wong4, Bevan Sawatsky4, Shyam Ramachandran3, Paul B. McCray, Jr.3, Klaus Cichutek1, Veronika von Messling4,5, Marc Lopez6 and Roberto Cattaneo2

1 Paul-Ehrlich-Institut Langen, Germany. 2 Mayo Clinic, Rochester, Minnesota, USA. 3 University of Iowa, Iowa City, Iowa, USA. 4 INRS and Institut Armand Frappier, Montreal, Canada. 5 Duke University and National University of Singapore, Singapore. 6 INSERM, UMR891/CRCM and University of Aix-Marseille, Marseille, France

Sneezing and coughing transmit measles, a highly contagious respiratory virus. In the airways, measles infects immune cells that ferry it to the lymphatic organs, where it replicates vigorously. How and where the virus crosses back into the airways has remained unknown. Based on functional analyses of surface proteins preferentially expressed on virus-permissive epithelial cell lines, we identified nectin-4 (poliovirus-receptor-like-4) as a candidate receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein hemagglutinin with high affinity through its membrane-distal domain. Nectin-4 sustains non-cytopathic lateral virus spread in well-differentiated primary human airway epithelia infected basolaterally, and facilitates virus emergence into the trachea of cynomolgus macaques. While viruses target other receptors to initiate infection and transit through barriers, nectin-4 is exploited for site-directed host escape. Nectin-4 is a cellular marker of several types of cancer, which has implications for the ongoing development of measles virus for oncolysis.