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

Abstract

Nectin-4 is identified as a receptor for measles virus on epithelial cells, and measles virus might use nectin-4 for emergence in the airways. Nectin-4, a cellular adhesion molecule that is highly expressed in lung, breast and ovarian cancer, is shown here to act as a receptor for measles virus on epithelial cells. The findings suggest that measles virus might use nectin-4 for emergence in the airways. Attenuated measles viruses are attracting attention as potential oncolytic agents, and are known to replicate preferentially in cancer cells, so this latest work could have important implications for cancer therapy. 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.