Tumor Cell Marker PVRL4 (Nectin 4) Is an Epithelial Cell Receptor for Measles Virus

Abstract

Vaccine and laboratory adapted strains of measles virus can use CD46 as a receptor to infect many human cell lines. However, wild type isolates of measles virus cannot use CD46, and they infect activated lymphocytes, dendritic cells, and macrophages via the receptor CD150/SLAM. Wild type virus can also infect epithelial cells of the respiratory tract through an unidentified receptor. We demonstrate that wild type measles virus infects primary airway epithelial cells grown in fetal calf serum and many adenocarcinoma cell lines of the lung, breast, and colon. Transfection of non-infectable adenocarcinoma cell lines with an expression vector encoding CD150/SLAM rendered them susceptible to measles virus, indicating that they were virus replication competent, but lacked a receptor for virus attachment and entry. Microarray analysis of susceptible versus non-susceptible cell lines was performed, and comparison of membrane protein gene transcripts produced a list of 11 candidate receptors. Of these, only the human tumor cell marker PVRL4 (Nectin 4) rendered cells amenable to measles virus infections. Flow cytometry confirmed that PVRL4 is highly expressed on the surfaces of susceptible lung, breast, and colon adenocarcinoma cell lines. Measles virus preferentially infected adenocarcinoma cell lines from the apical surface, although basolateral infection was observed with reduced kinetics. Confocal immune fluorescence microscopy and surface biotinylation experiments revealed that PVRL4 was expressed on both the apical and basolateral surfaces of these cell lines. Antibodies and siRNA directed against PVRL4 were able to block measles virus infections in MCF7 and NCI-H358 cancer cells. A virus binding assay indicated that PVRL4 was a bona fide receptor that supported virus attachment to the host cell. Several strains of measles virus were also shown to use PVRL4 as a receptor. Measles virus infection reduced PVRL4 surface expression in MCF7 cells, a property that is characteristic of receptor-associated viral infections.

Infection of lymphoid tissues in the macaque upper respiratory tract contributes to the emergence of transmissible measles virus

“…The identification of CD150 as the primary MV cellular receptor on activated B-and Tlymphocytes, macrophages and mature dendritic cells (Tatsuo et al, 2000) explains the largely lymphotropic nature of measles. The more recent discovery that PVRL4 (Nectin 4), a component of the adherens junction, is also a bona fide MV cellular receptor (Mühlebach et al, 2011;Noyce et al, 2011) explains the epitheliotropism observed in the late stages of the disease (Ludlow et al, 2010(Ludlow et al, , 2013.…”

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 .…”