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

Abstract

Measles (MV) is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths1,2. While it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to initially infect macrophages and dendritic cells of the airways using the signaling lymphocytic activation molecule (SLAM, CD150) as receptor3-6. These cells then cross the respiratory epithelium and ferry the infection to lymphatic organs where MV replicates vigorously7. 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-48 (poliovirus-receptor-like-4) 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 MV entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is down-regulated in infected epithelial cells, including those of macaque tracheas. While other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that MV targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer9-11, which has implications for ongoing MV-based clinical trials of oncolysis12.

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

“…More recently, nectin-4 was identified as an entry point for measles and other viruses and was proposed as a target for oncolytic viral therapy (21,22). Although several groups reported the detection of nectin-4 expression in breast, ovarian, and lung cancers (23)(24)(25)(26), no comprehensive analysis has been reported to date.…”

Dendritic cell subsets involved in type I IFN induction in mouse measles virus infection models

“…However, the expression pattern of CD150 does not explain why WT strains of MV infect epithelial cells that do not express CD150. Recently, human nectin-4 (also called poliovirus receptor-related 4, PVRL4) was identified as the third entry receptor for WT strains of MV (Mühlebach et al, 2011, Noyce et al, 2011. Expression of nectin-4 is restricted to the basolateral surface of epithelial cells (Delpeut et al, 2012).…”

Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

“…Three different cell surface receptors have been identified to interact with MV envelope glycoprotein hemagglutinin (H), permitting viral entry into cells: CD46 for laboratory MV strains 12,13 , CD150 for both wild-type (wt) and laboratory MV strains 14 , and nectin-4 (PVRL4), recently shown to mediate the viral egress from the respiratory tract 15,16 . CD150 (IPO-3 or SLAM, for Signaling Lymphocytic Activation Molecule) is a transmembrane protein which in humans is encoded by the SLAMF1 gene and is expressed on activated T and B cells, DCs, and monocytes 17,18 .…”