Measles Virus Infects both Polarized Epithelial and Immune Cells by Using Distinctive Receptor-Binding Sites on Its Hemagglutinin

Abstract

Measles is one of the most contagious human infectious diseases and remains a major cause of childhood morbidity and mortality worldwide. The signaling lymphocyte activation molecule (SLAM), also called CD150, is a cellular receptor for measles virus (MV), presumably accounting for its tropism for immune cells and its immunosuppressive properties. On the other hand, pathological studies have shown that MV also infects epithelial cells at a later stage of infection, although its mechanism has so far been unknown. In this study, we show that wild-type MV can infect and produce syncytia in human polarized epithelial cell lines independently of SLAM and CD46 (a receptor for the vaccine strains of MV). Progeny viral particles are released exclusively from the apical surface of these polarized epithelial cell lines. We have also identified amino acid residues on the MV attachment protein that are likely to interact with a putative receptor on epithelial cells. All of these residues have aromatic side chains and may form a receptor-binding pocket located in a different position from the putative SLAM-and CD46-binding sites on the MV attachment protein. Thus, our results indicate that MV has an intrinsic ability to infect both polarized epithelial and immune cells by using distinctive receptorbinding sites on the attachment protein corresponding to each of their respective receptors. The ability of MV to infect polarized epithelial cells and its exclusive release from the apical surface may facilitate its efficient transmission via aerosol droplets, resulting in its highly contagious nature.Measles remains a major cause of childhood morbidity and mortality worldwide despite the availability of efficacious vaccines. Measles virus (MV), an enveloped RNA virus belonging to the genus Morbillivirus in the family Paramyxoviridae, is transmitted via aerosol droplets and considered to be one of the most contagious human pathogens. MV has two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins, which are responsible for receptor binding and membrane fusion, respectively (18). MV enters a cell by membrane fusion at the cell surface. The attachment of the H protein to a cellular receptor is believed to induce the conformational change of the H protein, as well as that of the F protein, which promotes the fusion of the viral envelope with the host cell membrane. MV also causes cell-cell fusion in susceptible cells. The signaling lymphocyte activation molecule (SLAM), also known as CD150, has been identified as a receptor for MV (10,21,47). SLAM is expressed on immune cells, such as activated lymphocytes, mature dendritic cells, and macrophages, providing a good explanation for the lymphotropism and immunosuppressive nature of MV (4, 51). Although CD46, a ubiquitously expressed complement regulatory molecule, functions as a receptor for the vaccine strains of MV (8, 30), a great majority of viruses circulating in measles patients use SLAM, but not CD46, as a receptor (35,51). A recent study of MV infection in macaq...

Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed

“…In this alternative model, crossing occurs only from the basolateral to the apical side, suggesting that the elusive epithelial receptor (EpR) is located basolaterally. Consistent with this prediction, studies based on transformed cell lines reported that formation of a polarized monolayer interfered with apical infection (11,12). Moreover, studies based on primary well-differentiated human airway epithelium showed that a vaccine strain MV preferentially infects these epithelia from the basolateral surface (13), but the question of the polarity of infection of wild-type MV was not asked in this system.…”

“…Recently, Tahara et al (12) identified F483, Y541, and Y543 as necessary for EpR-dependent fusion. We also found that mutation of Y541 or Y543 interferes with EpR-dependent fusion but noted that Y541 also reduces SLAM-dependent fusion.…”

Pseudotyping lentiviral vectors with the wild-type measles virus glycoproteins improves titer and selectivity

“…Interestingly, this was also the case on the human bronchioalveolar carcinoma cell line NCI-H358 (ATCC CRL-5807), previously shown to express beside CD46 the EpR (Table 1). 7,11 Thus, the EpR must be at least as efficient as CD46 in mediating F/H-dependent cell entry.…”

“…Human small airway epithelial cells (Lonza Verviers S.p.r.l., Belgium), which are permissive for infection by MV WT in the absence of SLAM, 7,11,21 were transduced by MV WT -HIV particles with at least the same efficiency as VSV-G-HIV particles (6.7 vs 3.4%, respectively; Figure 3a). These results were confirmed with small airway epithelial cells from a second donor (data not shown).…”

“…10 An unidentified receptor (EpR) is used by MV in late stages of infection, when MV infects airway epithelial cells and sheds from the respiratory system. 7,11,12 We hypothesized that lentiviral vectors pseudotyped with the envelope proteins of WT MV will exhibit the tropism of clinical MV isolates, that is use SLAM and EpR for cell entry. The data show that MV WT -HIV vectors exhibit a restricted tropism for activated lymphocytes and epithelial cells and can be generated at substantially higher titers than MV Vac -HIV vectors.…”