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The Host Cell Receptors for Measles Virus and Their Interaction with the Viral Hemagglutinin (H) Protein

View Article: PubMed Central - PubMed

ABSTRACT

The hemagglutinin (H) protein of measles virus (MeV) interacts with a cellular receptor which constitutes the initial stage of infection. Binding of H to this host cell receptor subsequently triggers the F protein to activate fusion between virus and host plasma membranes. The search for MeV receptors began with vaccine/laboratory virus strains and evolved to more relevant receptors used by wild-type MeV. Vaccine or laboratory strains of measles virus have been adapted to grow in common cell lines such as Vero and HeLa cells, and were found to use membrane cofactor protein (CD46) as a receptor. CD46 is a regulator that normally prevents cells from complement-mediated self-destruction, and is found on the surface of all human cells, with the exception of erythrocytes. Mutations in the H protein, which occur during adaptation and allow the virus to use CD46 as a receptor, have been identified. Wild-type isolates of measles virus cannot use the CD46 receptor. However, both vaccine/laboratory and wild-type strains can use an immune cell receptor called signaling lymphocyte activation molecule family member 1 (SLAMF1; also called CD150) and a recently discovered epithelial receptor known as Nectin-4. SLAMF1 is found on activated B, T, dendritic, and monocyte cells, and is the initial target for infections by measles virus. Nectin-4 is an adherens junction protein found at the basal surfaces of many polarized epithelial cells, including those of the airways. It is also over-expressed on the apical and basal surfaces of many adenocarcinomas, and is a cancer marker for metastasis and tumor survival. Nectin-4 is a secondary exit receptor which allows measles virus to replicate and amplify in the airways, where the virus is expelled from the body in aerosol droplets. The amino acid residues of H protein that are involved in binding to each of the receptors have been identified through X-ray crystallography and site-specific mutagenesis. Recombinant measles “blind” to each of these receptors have been constructed, allowing the virus to selectively infect receptor specific cell lines. Finally, the observations that SLAMF1 is found on lymphomas and that Nectin-4 is expressed on the cell surfaces of many adenocarcinomas highlight the potential of measles virus for oncolytic therapy. Although CD46 is also upregulated on many tumors, it is less useful as a target for cancer therapy, since normal human cells express this protein on their surfaces.

No MeSH data available.


Related in: MedlinePlus

Microarray analysis reveals that Nectin-4 is a receptor for wild type MeV. (A) Comparative microarray analysis of mRNAs from permissive versus non-permissive cancer cell lines and SAECs grown in the presence or absence of 2% fetal calf serum revealed 11 candidate cellular receptors; (B) COS-1 monkey kidney cells were transfected with expression plasmids encoding PVRL4 (Nectin-4), CD150 (SLAMF1), solute carrier family 6 member 14 (SLC6A14), six transmembrane epithelial antigen of prostate 4 (STEAP4), transmembrane serine protease 11E (TMPRSS11E), mucin 1 (MUC1), erb-b2 receptor tyrosine kinase 3 (ERBB3), and mucin 20 (MUC20) genes. After 36 h, cells were infected with wild type IC-323 MeV expressing the eGFP reporter protein. Only PVRL4 (Nectin-4) and CD150 (SLAMF1) expression supported wtMeV infection of the COS-1 host cells. Fluorescence micrographs were taken at 36 h post-infection; (C) COS-1 cells were transfected with expression plasmids encoding PVRL4 (Nectin-4), poliovirus receptor (PVR), PVRL1 (Nectin-1), PVRL2 (Nectin-2), and PVRL3 (Nectin-3). Only PVRL4 (Nectin-4) expression supported wtMeV infection. Reprinted by the author from PLoS Pathogens under the Creative Commons Attribution agreement from: Noyce, R.S.; Bondre, D.G.; Ha, M.N.; Lin, L.T.; Sisson, G.; Tsao, M.S.; Richardson, C.D. PLoS Pathog. 2011, 7, e1002240 [133].
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viruses-08-00250-f009: Microarray analysis reveals that Nectin-4 is a receptor for wild type MeV. (A) Comparative microarray analysis of mRNAs from permissive versus non-permissive cancer cell lines and SAECs grown in the presence or absence of 2% fetal calf serum revealed 11 candidate cellular receptors; (B) COS-1 monkey kidney cells were transfected with expression plasmids encoding PVRL4 (Nectin-4), CD150 (SLAMF1), solute carrier family 6 member 14 (SLC6A14), six transmembrane epithelial antigen of prostate 4 (STEAP4), transmembrane serine protease 11E (TMPRSS11E), mucin 1 (MUC1), erb-b2 receptor tyrosine kinase 3 (ERBB3), and mucin 20 (MUC20) genes. After 36 h, cells were infected with wild type IC-323 MeV expressing the eGFP reporter protein. Only PVRL4 (Nectin-4) and CD150 (SLAMF1) expression supported wtMeV infection of the COS-1 host cells. Fluorescence micrographs were taken at 36 h post-infection; (C) COS-1 cells were transfected with expression plasmids encoding PVRL4 (Nectin-4), poliovirus receptor (PVR), PVRL1 (Nectin-1), PVRL2 (Nectin-2), and PVRL3 (Nectin-3). Only PVRL4 (Nectin-4) expression supported wtMeV infection. Reprinted by the author from PLoS Pathogens under the Creative Commons Attribution agreement from: Noyce, R.S.; Bondre, D.G.; Ha, M.N.; Lin, L.T.; Sisson, G.; Tsao, M.S.; Richardson, C.D. PLoS Pathog. 2011, 7, e1002240 [133].

Mentions: Nectin-4/PVRL4 was recently shown by our laboratory, and confirmed by Cattaneo’s group, to be the elusive epithelial receptor for MeV [133,138]. We showed that wtMeV infected primary airway epithelial cells grown in fetal calf serum, and many lung, breast, and colon adenocarcinoma cell lines. Adenocarcinomas are defined as tumors with glandular histology that arise from epithelial cells. The virus receptor appeared to be on the apical surface of permissive cancer cells, as well as the basolateral surface. Many cancer cell lines that were susceptible to wtMeV are polarized, yet disruption of adherens and tight junctions with phorbol esters had no effect upon viral infections. Transfection of several non-permissive cancer cell lines (MDA-MB-231 and A549 cells) with an expression vector encoding SLAMF1 rendered them susceptible to measles virus. This indicated that these adenocarcinoma cells were virus replication competent, but lacked a receptor needed for virus infection. Microarray analysis of permissive versus non-permissive cell lines, and a comparison of the mRNA transcripts for membrane proteins, led us to compile a list of 11 candidate receptors. Only the human tumor cell marker Nectin-4/PVRL4 made cells permissive to MeV (Figure 9). Flow cytometry confirmed that Nectin-4 was expressed on the surfaces of permissive adenocarcinoma cell lines. Antibodies and small interfering RNA (siRNA) directed against Nectin-4 were capable of blocking measles virus infections in the MCF7 breast adenocarcinoma cell line. In addition, a direct virus binding assay using flow cytometry, indicated that Nectin-4 was a bona fide receptor that supported virus attachment to the host cell. We subsequently observed that both human Nectin-4 and its mouse homologue could function as receptors since this molecule is highly conserved across species. Several different laboratory and wild-type strains of measles were tested, and all were able to use Nectin-4 as a receptor.


The Host Cell Receptors for Measles Virus and Their Interaction with the Viral Hemagglutinin (H) Protein
Microarray analysis reveals that Nectin-4 is a receptor for wild type MeV. (A) Comparative microarray analysis of mRNAs from permissive versus non-permissive cancer cell lines and SAECs grown in the presence or absence of 2% fetal calf serum revealed 11 candidate cellular receptors; (B) COS-1 monkey kidney cells were transfected with expression plasmids encoding PVRL4 (Nectin-4), CD150 (SLAMF1), solute carrier family 6 member 14 (SLC6A14), six transmembrane epithelial antigen of prostate 4 (STEAP4), transmembrane serine protease 11E (TMPRSS11E), mucin 1 (MUC1), erb-b2 receptor tyrosine kinase 3 (ERBB3), and mucin 20 (MUC20) genes. After 36 h, cells were infected with wild type IC-323 MeV expressing the eGFP reporter protein. Only PVRL4 (Nectin-4) and CD150 (SLAMF1) expression supported wtMeV infection of the COS-1 host cells. Fluorescence micrographs were taken at 36 h post-infection; (C) COS-1 cells were transfected with expression plasmids encoding PVRL4 (Nectin-4), poliovirus receptor (PVR), PVRL1 (Nectin-1), PVRL2 (Nectin-2), and PVRL3 (Nectin-3). Only PVRL4 (Nectin-4) expression supported wtMeV infection. Reprinted by the author from PLoS Pathogens under the Creative Commons Attribution agreement from: Noyce, R.S.; Bondre, D.G.; Ha, M.N.; Lin, L.T.; Sisson, G.; Tsao, M.S.; Richardson, C.D. PLoS Pathog. 2011, 7, e1002240 [133].
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Related In: Results  -  Collection

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viruses-08-00250-f009: Microarray analysis reveals that Nectin-4 is a receptor for wild type MeV. (A) Comparative microarray analysis of mRNAs from permissive versus non-permissive cancer cell lines and SAECs grown in the presence or absence of 2% fetal calf serum revealed 11 candidate cellular receptors; (B) COS-1 monkey kidney cells were transfected with expression plasmids encoding PVRL4 (Nectin-4), CD150 (SLAMF1), solute carrier family 6 member 14 (SLC6A14), six transmembrane epithelial antigen of prostate 4 (STEAP4), transmembrane serine protease 11E (TMPRSS11E), mucin 1 (MUC1), erb-b2 receptor tyrosine kinase 3 (ERBB3), and mucin 20 (MUC20) genes. After 36 h, cells were infected with wild type IC-323 MeV expressing the eGFP reporter protein. Only PVRL4 (Nectin-4) and CD150 (SLAMF1) expression supported wtMeV infection of the COS-1 host cells. Fluorescence micrographs were taken at 36 h post-infection; (C) COS-1 cells were transfected with expression plasmids encoding PVRL4 (Nectin-4), poliovirus receptor (PVR), PVRL1 (Nectin-1), PVRL2 (Nectin-2), and PVRL3 (Nectin-3). Only PVRL4 (Nectin-4) expression supported wtMeV infection. Reprinted by the author from PLoS Pathogens under the Creative Commons Attribution agreement from: Noyce, R.S.; Bondre, D.G.; Ha, M.N.; Lin, L.T.; Sisson, G.; Tsao, M.S.; Richardson, C.D. PLoS Pathog. 2011, 7, e1002240 [133].
Mentions: Nectin-4/PVRL4 was recently shown by our laboratory, and confirmed by Cattaneo’s group, to be the elusive epithelial receptor for MeV [133,138]. We showed that wtMeV infected primary airway epithelial cells grown in fetal calf serum, and many lung, breast, and colon adenocarcinoma cell lines. Adenocarcinomas are defined as tumors with glandular histology that arise from epithelial cells. The virus receptor appeared to be on the apical surface of permissive cancer cells, as well as the basolateral surface. Many cancer cell lines that were susceptible to wtMeV are polarized, yet disruption of adherens and tight junctions with phorbol esters had no effect upon viral infections. Transfection of several non-permissive cancer cell lines (MDA-MB-231 and A549 cells) with an expression vector encoding SLAMF1 rendered them susceptible to measles virus. This indicated that these adenocarcinoma cells were virus replication competent, but lacked a receptor needed for virus infection. Microarray analysis of permissive versus non-permissive cell lines, and a comparison of the mRNA transcripts for membrane proteins, led us to compile a list of 11 candidate receptors. Only the human tumor cell marker Nectin-4/PVRL4 made cells permissive to MeV (Figure 9). Flow cytometry confirmed that Nectin-4 was expressed on the surfaces of permissive adenocarcinoma cell lines. Antibodies and small interfering RNA (siRNA) directed against Nectin-4 were capable of blocking measles virus infections in the MCF7 breast adenocarcinoma cell line. In addition, a direct virus binding assay using flow cytometry, indicated that Nectin-4 was a bona fide receptor that supported virus attachment to the host cell. We subsequently observed that both human Nectin-4 and its mouse homologue could function as receptors since this molecule is highly conserved across species. Several different laboratory and wild-type strains of measles were tested, and all were able to use Nectin-4 as a receptor.

View Article: PubMed Central - PubMed

ABSTRACT

The hemagglutinin (H) protein of measles virus (MeV) interacts with a cellular receptor which constitutes the initial stage of infection. Binding of H to this host cell receptor subsequently triggers the F protein to activate fusion between virus and host plasma membranes. The search for MeV receptors began with vaccine/laboratory virus strains and evolved to more relevant receptors used by wild-type MeV. Vaccine or laboratory strains of measles virus have been adapted to grow in common cell lines such as Vero and HeLa cells, and were found to use membrane cofactor protein (CD46) as a receptor. CD46 is a regulator that normally prevents cells from complement-mediated self-destruction, and is found on the surface of all human cells, with the exception of erythrocytes. Mutations in the H protein, which occur during adaptation and allow the virus to use CD46 as a receptor, have been identified. Wild-type isolates of measles virus cannot use the CD46 receptor. However, both vaccine/laboratory and wild-type strains can use an immune cell receptor called signaling lymphocyte activation molecule family member 1 (SLAMF1; also called CD150) and a recently discovered epithelial receptor known as Nectin-4. SLAMF1 is found on activated B, T, dendritic, and monocyte cells, and is the initial target for infections by measles virus. Nectin-4 is an adherens junction protein found at the basal surfaces of many polarized epithelial cells, including those of the airways. It is also over-expressed on the apical and basal surfaces of many adenocarcinomas, and is a cancer marker for metastasis and tumor survival. Nectin-4 is a secondary exit receptor which allows measles virus to replicate and amplify in the airways, where the virus is expelled from the body in aerosol droplets. The amino acid residues of H protein that are involved in binding to each of the receptors have been identified through X-ray crystallography and site-specific mutagenesis. Recombinant measles “blind” to each of these receptors have been constructed, allowing the virus to selectively infect receptor specific cell lines. Finally, the observations that SLAMF1 is found on lymphomas and that Nectin-4 is expressed on the cell surfaces of many adenocarcinomas highlight the potential of measles virus for oncolytic therapy. Although CD46 is also upregulated on many tumors, it is less useful as a target for cancer therapy, since normal human cells express this protein on their surfaces.

No MeSH data available.


Related in: MedlinePlus