SLAM (CD150)-independent measles virus entry as revealed by recombinant virus expressing green fluorescent protein.
Journal: 2002/July - Journal of Virology
ISSN: 0022-538X
PUBMED: 12050387
Abstract:
Wild-type measles virus (MV) strains use human signaling lymphocyte activation molecule (SLAM) as a cellular receptor, while vaccine strains such as the Edmonston strain can use both SLAM and CD46 as receptors. Although the expression of SLAM is restricted to cells of the immune system (lymphocytes, dendritic cells, and monocytes), histopathological studies with humans and experimentally infected monkeys have shown that MV also infects SLAM-negative cells, including epithelial, endothelial, and neuronal cells. In an attempt to explain these findings, we produced the enhanced green fluorescent protein (EGFP)-expressing recombinant MV (IC323-EGFP) based on the wild-type IC-B strain. IC323-EGFP showed almost the same growth kinetics as the parental recombinant MV and produced large syncytia exhibiting green autofluorescence in SLAM-positive cells. Interestingly, all SLAM-negative cell lines examined also showed green autofluorescence after infection with IC323-EGFP, although the virus hardly spread from the originally infected individual cells and thus did not induce syncytia. When the number of EGFP-expressing cells after infection was taken as an indicator, the infectivities of IC323-EGFP for SLAM-negative cells were 2 to 3 logs lower than those for SLAM-positive cells. Anti-MV hemagglutinin antibody or fusion block peptide, but not anti-CD46 antibody, blocked IC323-EGFP infection of SLAM-negative cells. This infection occurred under conditions in which entry via endocytosis was inhibited. These results indicate that MV can infect a variety of cells, albeit with a low efficiency, by using an as yet unidentified receptor(s) other than SLAM or CD46, in part explaining the observed MV infection of SLAM-negative cells in vivo.
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J Virol 76(13): 6743-6749

SLAM (CD150)-Independent Measles Virus Entry as Revealed by Recombinant Virus Expressing Green Fluorescent Protein

Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Department of Virus Diseases and Vaccine Control, National Institute of Infectious Diseases, Musashi-murayama, Tokyo 208-0011, Japan2
Corresponding author. Mailing address: Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan. Phone: 81-92-642-6135. Fax: 81-92-642-6140. E-mail: pj.ca.u-uhsuyk.dem.ygoloriv@iganayy.
Received 2002 Jan 8; Accepted 2002 Apr 4.

Abstract

Wild-type measles virus (MV) strains use human signaling lymphocyte activation molecule (SLAM) as a cellular receptor, while vaccine strains such as the Edmonston strain can use both SLAM and CD46 as receptors. Although the expression of SLAM is restricted to cells of the immune system (lymphocytes, dendritic cells, and monocytes), histopathological studies with humans and experimentally infected monkeys have shown that MV also infects SLAM-negative cells, including epithelial, endothelial, and neuronal cells. In an attempt to explain these findings, we produced the enhanced green fluorescent protein (EGFP)-expressing recombinant MV (IC323-EGFP) based on the wild-type IC-B strain. IC323-EGFP showed almost the same growth kinetics as the parental recombinant MV and produced large syncytia exhibiting green autofluorescence in SLAM-positive cells. Interestingly, all SLAM-negative cell lines examined also showed green autofluorescence after infection with IC323-EGFP, although the virus hardly spread from the originally infected individual cells and thus did not induce syncytia. When the number of EGFP-expressing cells after infection was taken as an indicator, the infectivities of IC323-EGFP for SLAM-negative cells were 2 to 3 logs lower than those for SLAM-positive cells. Anti-MV hemagglutinin antibody or fusion block peptide, but not anti-CD46 antibody, blocked IC323-EGFP infection of SLAM-negative cells. This infection occurred under conditions in which entry via endocytosis was inhibited. These results indicate that MV can infect a variety of cells, albeit with a low efficiency, by using an as yet unidentified receptor(s) other than SLAM or CD46, in part explaining the observed MV infection of SLAM-negative cells in vivo.

Abstract

Measles virus (MV) is an enveloped virus of the Morbillivirus genus in the Paramyxoviridae family and has a linear, nonsegmented, negative-strand RNA genome with two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins (12). Despite the development of effective live vaccines, measles remains a significant cause of infant mortality worldwide, mainly due to secondary infections caused by MV-induced immunosuppression (12).

Vaccine strains of MV such as the Edmonston strain use human CD46 as a cellular receptor (9, 25). Since CD46 is expressed on all nucleated human cells (19), vaccine strains of MV can infect almost any human cell line. In contrast, wild-type strains of MV isolated in the marmoset B-cell line B95a or human B-cell lines are usually unable to use CD46 as a receptor (6, 13, 17, 18, 36, 37, 46, 47). Recently, we have demonstrated that signaling lymphocyte activation molecule (SLAM; also known as CD150) acts as a cellular receptor for both vaccine and wild-type strains of MV (48). SLAM is a costimulatory molecule in lymphocyte activation (7), and its expression is restricted to activated T and B lymphocytes, immature thymocytes (7, 41), mature dendritic cells (26), and activated monocytes (23), nicely explaining the tropism of MV as well as the lymphopenia and immunosuppression observed in MV infection. We have also reported that viruses obtained from clinical specimens (throat swabs of measles patients) use SLAM but not CD46 as a receptor (28). Previous histopathological studies in vivo, however, have revealed that in addition to infecting SLAM-positive cells of the immune system, MV also infects endothelial (11, 15, 16, 21, 24), epithelial (21, 24, 44), and neuronal cells (3, 24, 40), none of which have been shown to express SLAM (7, 41). Thus, the in vivo receptor usage of MV remains to be determined.

Reverse genetics technology has enabled us to study a number of important problems concerning virus replication and pathogenesis. As for MV, the rescue of the Edmonston strain from cloned DNA was developed in 1995 (32), providing us with many insights into MV biology (10, 30, 31, 35, 49, 50). However, since the vaccine strain does not exhibit pathogenicity in experimentally infected monkeys (1, 17), results obtained with it may not be applicable to clinical problems in vivo. Recently, Takeda et al. have successfully developed the rescue system of a wild-type MV strain that could reproduce the natural course of MV pathology in monkeys, opening the way to molecularly dissecting the pathogenesis of MV infection at the level of viral genomes (45).

In this study, we examined MV entry into SLAM-negative cells. To facilitate the analysis, we recovered a wild-type strain of MV expressing the enhanced green fluorescent protein (EGFP) by using reverse genetics technology and determined its infectivities for various cell lines. The results indicate that wild-type MV can infect SLAM-negative cells, albeit with a low efficiency, via a novel pathway independent of known MV receptors such as SLAM and CD46.

Acknowledgments

We thank M. A. Billeter, M. A. Whitt, W. Britt, J. Vieira, and T. Seya for providing reagents.

This work was supported by grants from the Ministry of Education, Science and Culture of Japan and from the Organization for Drug ADR Relief, R&D Promotion and Product Review of Japan.

Acknowledgments

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