A Human Lung Carcinoma Cell Line Supports Efficient Measles Virus Growth and Syncytium Formation via a SLAM- and CD46-Independent Mechanism

Abstract

Measles virus (MV) propagates mainly in lymphoid organs throughout the body and produces syncytia by using signaling lymphocyte activation molecule (SLAM) as a receptor. MV also spreads in SLAM-negative epithelial tissues by unknown mechanisms. Ubiquitously expressed CD46 functions as another receptor for vaccine strains of MV but not for wild-type strains. We here show that MV grows and produces syncytia efficiently in a human lung adenocarcinoma cell line via a SLAM-and CD46-independent mechanism using a novel receptor-binding site on the hemagglutinin protein. This infection model could advance our understanding of MV infection of SLAM-negative epithelial cells and tissues.Measles is an acute, contagious disease characterized by high fever, cough, and a maculopapular rash (8). The etiologic agent is Measles virus (MV), which belongs to the genus Morbillivirus in the family Paramyxoviridae. MV initiates its infectious cycle by attaching the hemagglutinin (H) protein on the virus envelope to a cellular receptor on a target cell. Attachment of the H protein to a receptor triggers membrane fusion between the virus envelope and the plasma membrane of the target cell mediated by the fusion (F) protein (14). The signaling lymphocyte activation molecule (SLAM) (also known as CD150) and CD46 have been identified as receptors for MV (5,6,10,22,47). SLAM is a common receptor for all strains of MV, whereas CD46 functions as a receptor for only vaccine strains and some laboratory strains of MV (52). Ono et al. showed that MV strains circulating in patients (wild-type [wt] MV strains) use SLAM but not CD46 (26). Formation of syncytia is characteristic of MV-infected cells (8). SLAM is also required for this process by wt MV (52).Pathological examination of patients and monkeys infected with MV has indicated that lymphoid organs are major targets of MV (3,23,28,49,51), and the distribution of SLAM is well correlated with sites of MV spread in vivo (52). Pathological data also show that MV antigens and syncytia are detected in epithelial tissues in various organs, such as the skin, esophagus, oral mucosa, trachea, intestines, pharynx, and urinary bladder (4, 12, 15, 16, 20, 23-25, 28, 34). Therefore, epithelial tissues are likely targets of MV, as are lymphoid organs in vivo. Previous studies using a panel of cell lines showed that only SLAM-positive cells support efficient wt MV infection and syncytium formation (43,46). Although studies have shown a low level of SLAM-independent infection by wt MV in various cell lines (the efficiency was 100 to 1,000 times lower than that * Corresponding author. Mailing address:

Wild-type measles virus infection of primary epithelial cells occurs via the basolateral surface without syncytium formation or release of infectious virus

“…A number of recent studies investigating MV infection of epithelial cells have focused on in vitro model systems (Tahara et al, 2008;Takeda et al, 2007) or have utilized the macaque model of measles in the absence of histological or pathological analysis of MV-infected tissues (Leonard et al, 2008). These studies have identified specific amino acids of the MV haemagglutinin (H) glycoprotein that are involved in the binding of H to a putative receptor (EpR) on the basolateral surface of epithelial cells and suggest a critical role for epithelial cells in mediating MV transmission.…”

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

“…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.…”

Sorting signals in the measles virus wild-type glycoproteins differently influence virus spread in polarized epithelia and lymphocytes

“…It is generally accepted that vaccine strains are able to use CD46 and CD150/SLAM for cell entry, whereas wild-type strains can use only CD150/SLAM; this is in agreement with the well-known lymphotropism of MV wild-type infections in vivo (for a review see Yanagi et al, 2006). In addition to CD46 and CD150/SLAM, there is evidence for an additional receptor on epithelial cells (Tahara et al, 2008;Takeda et al, 2007).…”