Measles virus continues to be a major killer of children, claiming roughly one million lives a year. Measles virus infection causes profound immunosuppression, which makes measles patients susceptible to secondary infections accounting for high morbidity and mortality. The Edmonston strain of measles virus, and vaccine strains derived from it, use as a cellular receptor human CD46 (refs 3, 4), which is expressed on all nucleated cells; however, most clinical isolates of measles virus cannot use CD46 as a receptor. Here we show that human SLAM (signalling lymphocyte-activation molecule; also known as CDw150), a recently discovered membrane glycoprotein expressed on some T and B cells, is a cellular receptor for measles virus, including the Edmonston strain. Transfection with a human SLAM complementary DNA enables non-susceptible cell lines to bind measles virus, support measles virus replication and develop cytopathic effects. The distribution of SLAM on various cell lines is consistent with their susceptibility to clinical isolates of measles virus. The identification of SLAM as a receptor for measles virus opens the way to a better understanding of the pathogenesis of measles virus infection, especially the immunosuppression induced by measles virus.
Measles virus (MV), a member of the Morbillivirus genus in the Paramyxoviridae family, causes an acute childhood disease which still claims roughly 1 million lives a year. MV is a nonsegmented negative-strand RNA virus with two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins (10). CD46 has been shown to be a cellular receptor for vaccine strains of MV such as the Edmonston and Halle strains (9, 25). These strains are capable of infecting all CD46-positive primate cell lines. However, recent clinical isolates of MV, which were usually isolated in the marmoset B-cell line B95a or human B-cell lines, were found to grow only in some primate B-and T-cell lines and human dendritic cells (11,12,14,16,32,33,37,38). By using vesicular stomatitis virus (VSV) pseudotypes bearing MV envelope proteins, we showed that virus entry is a major determinant of cell tropism of the Edmonston and B95a-isolated MV strains (38).Recently, expression cloning, combined with the VSV pseudotype system, allowed us to identify signaling lymphocytic activation molecule (SLAM; also known as CDw150) as a cellular receptor for MV (39). We showed that the cell surface expression of human SLAM (hSLAM) rendered rodent cells susceptible to all MV strains examined, including the Edmonston strain, B95a-isolated strains, peripheral blood mononuclear cell-isolated strains, and MV present in throat swabs from measles patients (39). SLAM, an important costimulatory molecule in lymphocyte activation, is expressed on some T and B cells (2,3,7,22,30,31,34), consistent with MV tropism and pathology including lymphopenia and immunosuppression (10). SLAM contains two highly glycosylated immunoglobulin (Ig) superfamily domains and has structural features placing it within the CD2 family, which includes CD2, CD48, CD58, 2B4, and Ly-9 (8). Like other members of the CD2 family, SLAM comprises an N-terminal membrane-distal V-set domain and a membrane-proximal C2-set domain, followed by the transmembrane segment (TM) and cytoplasmic tail (CY). A recent study showed that mouse SLAM (mSLAM) also shares molecular and functional characteristics with the human counterpart, with its predicted amino acid sequence exhibiting 58% similarity to that of hSLAM (6).In this study, we first examined whether mSLAM can act as a cellular receptor for MV, in an attempt to explain MV's inability to infect mice. We then defined the region of hSLAM that interacts with MV, by constructing various chimeric molecules. We also examined the interaction between MV envelope proteins and recombinant soluble forms of SLAM. The results indicated that the V domain of hSLAM, which binds the MV H protein, is essential for its function as an MV receptor. MATERIALS AND METHODS Cells and viruses.Derivations and culture conditions of cell lines used have been described elsewhere (38). The Edmonston (American Type Culture Collection) and KA (37) strains of MV were grown and titrated on Vero and B95a cells, respectively. Pseudotype viruses (VSV⌬G,ء VSV⌬G-ءEdHF, VSV⌬G-ء KAHF, and V...
Wild-type strains of measles virus (MV) isolated inB95a cells use the signalling lymphocyte activation molecule (SLAM ; also known as CD150) as a cellular receptor, whereas the Edmonston strain and its derivative vaccine strains can use both SLAM and the ubiquitously expressed CD46 as receptors. Among the major target cells for MV, lymphocytes and dendritic cells are known to express SLAM after activation, but monocytes have been reported to be SLAM-negative. In this study, SLAM expression on monocytes was examined under different conditions. When freshly isolated from the peripheral blood, monocytes did not express SLAM on the cell surface. However, monocytes became SLAM-positive after incubation with phytohaemagglutinin, bacterial lipopolysaccharide or MV. Anti-SLAM monoclonal antibodies efficiently blocked infection of activated monocytes with a wild-type strain of MV. These results indicate that SLAM is readily induced and acts as a monocyte receptor for MV.
Measles virus (MV) is efficiently isolated from patients with measles by using B95a cells, a marmoset B cell line. Recent wild-type MV strains isolated using B95a cells did not produce cytopathic effects in any of CD46+ primate cell lines examined (except B95a cells), nor did they induce downregulation of CD46. Transfection of the hemagglutinin (H) and fusion (F) genes of the Edmonston strain of MV produced syncytia in HeLa, Cos and B95a cells. By contrast, the expression of the H gene from the two wild-type strains, together with the F gene of the Edmonston strain, resulted in syncytium production in B95a cells, but not in HeLa and Cos cells. Cocultivation of Cos cells expressing the wild-type H protein and the Edmonston strain F protein with B95a cells, but not with HeLa, Jurkat or BJAB cells, generated large syncytia. The results suggest that these recent MV isolates may use a molecule other than CD46 as the cellular receptor or require another coreceptor to infect cells.
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