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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

Structure of the head region from the hemagglutinin (H) protein of measles virus (MeV). (A) View from the top of the H protein showing the six β-sheet regions of the propeller-like structure; (B) View of the H protein from the side showing the dimer formed through two cysteine linkages in the stem region. Arrows indicate central head region; (C) Amino acid sequence of the H protein from the IC-323 strain of MeV. The N481 (red) residue is mutated to Y481 in vaccine/laboratory strains of MeV, enabling H protein to bind to the CD46 receptor. Panel A is adapted with permission from the Nature Publishing Group, Macmillan Publishers Ltd: Colf, L.M.; Juo, Z.S.; Garcia, K.C. Nat. Struct. Mol. Biol2007, 14 1227–1228 [43]; Panel B is adapted from the American Society of Microbiology Journals: Rasbach, A.; Abel, T.; Münch, R.C.; Boller, K.; Schneider-Schaulies, J.; Buchholz, C.J. J. Virol.2013, 87, 6246–6255 [47].
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viruses-08-00250-f001: Structure of the head region from the hemagglutinin (H) protein of measles virus (MeV). (A) View from the top of the H protein showing the six β-sheet regions of the propeller-like structure; (B) View of the H protein from the side showing the dimer formed through two cysteine linkages in the stem region. Arrows indicate central head region; (C) Amino acid sequence of the H protein from the IC-323 strain of MeV. The N481 (red) residue is mutated to Y481 in vaccine/laboratory strains of MeV, enabling H protein to bind to the CD46 receptor. Panel A is adapted with permission from the Nature Publishing Group, Macmillan Publishers Ltd: Colf, L.M.; Juo, Z.S.; Garcia, K.C. Nat. Struct. Mol. Biol2007, 14 1227–1228 [43]; Panel B is adapted from the American Society of Microbiology Journals: Rasbach, A.; Abel, T.; Münch, R.C.; Boller, K.; Schneider-Schaulies, J.; Buchholz, C.J. J. Virol.2013, 87, 6246–6255 [47].

Mentions: Humans and some monkey species are hosts for MeV [15,16,17,18,19,20,21], while rodents are not normally infected by the virus [1,22,23,24,25]. MeV isolates were originally isolated and adapted to grow in laboratory primate cell lines (reviewed in [26]). In 1954, John Enders isolated a strain of measles virus from a young patient named David Edmonston using human kidney cells [27]. It was later adapted to continuous monkey kidney cell lines (Vero and CV-1), but the virus did not readily grow in non-primate cell lines. However, this virus was eventually passaged in chick embryo fibroblasts to yield the first measles attenuated virus vaccine [28,29,30,31,32]. Tissue-culture-cell-adapted virus isolates were found to agglutinate the red blood cells of most old world monkeys but not those of humans [33,34,35,36]. The laboratory-adapted Edmonston strain was primarily used to deduce the molecular properties of measles virus and the hemagglutination properties were assigned to one of the viral membrane glycoproteins. This surface glycoprotein from the adapted virus was named hemagglutinin (H) protein. The gene for H protein was first cloned in 1986 and its deduced sequence was reported [37]. Sequences for other vaccine and wild-type isolates were reported by the Center for Disease Control (CDC) [38,39,40]. It is a 617 amino acid type II glycoprotein anchored by a single membrane spanning region near its amino terminus. H protein from the Edmonston strain of MeV contains five potential N-linked glycosylation sites between amino acids 168 and 238 while H proteins from recent wild-type isolates have a sixth glycosylation site at amino acid 416. Glycosylation mediates folding and export of the glycoprotein. During the late 1990s, it became apparent that it was more relevant to study wild-type isolates of MeV and it has been observed that mutations including N481Y and E451V occur during the process of adaptation in cell culture [41,42]. These mutations confer the ability of the laboratory/vaccine strains to use CD46 as a receptor, whereas wild-type isolates do not. Structural studies using X-ray crystallography demonstrated that H protein consists of an α-helical stalk supporting a cubic-shaped six-blade β-propeller head structure [9,43]. Each of the blade domains contains four antiparallel β-strands connected sequentially through extended loops (Figure 1). The H protein of MeV forms disulfide-linked dimers on the viral surface that in turn associate to form tetramers [44]. H protein acts in association with F protein to activate fusion during entry and cell-to-cell transmission [13,45]. The fusion activity is associated with conformational changes in F protein that are triggered as H binds to its receptors (reviewed in [46]).


The Host Cell Receptors for Measles Virus and Their Interaction with the Viral Hemagglutinin (H) Protein
Structure of the head region from the hemagglutinin (H) protein of measles virus (MeV). (A) View from the top of the H protein showing the six β-sheet regions of the propeller-like structure; (B) View of the H protein from the side showing the dimer formed through two cysteine linkages in the stem region. Arrows indicate central head region; (C) Amino acid sequence of the H protein from the IC-323 strain of MeV. The N481 (red) residue is mutated to Y481 in vaccine/laboratory strains of MeV, enabling H protein to bind to the CD46 receptor. Panel A is adapted with permission from the Nature Publishing Group, Macmillan Publishers Ltd: Colf, L.M.; Juo, Z.S.; Garcia, K.C. Nat. Struct. Mol. Biol2007, 14 1227–1228 [43]; Panel B is adapted from the American Society of Microbiology Journals: Rasbach, A.; Abel, T.; Münch, R.C.; Boller, K.; Schneider-Schaulies, J.; Buchholz, C.J. J. Virol.2013, 87, 6246–6255 [47].
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5035964&req=5

viruses-08-00250-f001: Structure of the head region from the hemagglutinin (H) protein of measles virus (MeV). (A) View from the top of the H protein showing the six β-sheet regions of the propeller-like structure; (B) View of the H protein from the side showing the dimer formed through two cysteine linkages in the stem region. Arrows indicate central head region; (C) Amino acid sequence of the H protein from the IC-323 strain of MeV. The N481 (red) residue is mutated to Y481 in vaccine/laboratory strains of MeV, enabling H protein to bind to the CD46 receptor. Panel A is adapted with permission from the Nature Publishing Group, Macmillan Publishers Ltd: Colf, L.M.; Juo, Z.S.; Garcia, K.C. Nat. Struct. Mol. Biol2007, 14 1227–1228 [43]; Panel B is adapted from the American Society of Microbiology Journals: Rasbach, A.; Abel, T.; Münch, R.C.; Boller, K.; Schneider-Schaulies, J.; Buchholz, C.J. J. Virol.2013, 87, 6246–6255 [47].
Mentions: Humans and some monkey species are hosts for MeV [15,16,17,18,19,20,21], while rodents are not normally infected by the virus [1,22,23,24,25]. MeV isolates were originally isolated and adapted to grow in laboratory primate cell lines (reviewed in [26]). In 1954, John Enders isolated a strain of measles virus from a young patient named David Edmonston using human kidney cells [27]. It was later adapted to continuous monkey kidney cell lines (Vero and CV-1), but the virus did not readily grow in non-primate cell lines. However, this virus was eventually passaged in chick embryo fibroblasts to yield the first measles attenuated virus vaccine [28,29,30,31,32]. Tissue-culture-cell-adapted virus isolates were found to agglutinate the red blood cells of most old world monkeys but not those of humans [33,34,35,36]. The laboratory-adapted Edmonston strain was primarily used to deduce the molecular properties of measles virus and the hemagglutination properties were assigned to one of the viral membrane glycoproteins. This surface glycoprotein from the adapted virus was named hemagglutinin (H) protein. The gene for H protein was first cloned in 1986 and its deduced sequence was reported [37]. Sequences for other vaccine and wild-type isolates were reported by the Center for Disease Control (CDC) [38,39,40]. It is a 617 amino acid type II glycoprotein anchored by a single membrane spanning region near its amino terminus. H protein from the Edmonston strain of MeV contains five potential N-linked glycosylation sites between amino acids 168 and 238 while H proteins from recent wild-type isolates have a sixth glycosylation site at amino acid 416. Glycosylation mediates folding and export of the glycoprotein. During the late 1990s, it became apparent that it was more relevant to study wild-type isolates of MeV and it has been observed that mutations including N481Y and E451V occur during the process of adaptation in cell culture [41,42]. These mutations confer the ability of the laboratory/vaccine strains to use CD46 as a receptor, whereas wild-type isolates do not. Structural studies using X-ray crystallography demonstrated that H protein consists of an α-helical stalk supporting a cubic-shaped six-blade β-propeller head structure [9,43]. Each of the blade domains contains four antiparallel β-strands connected sequentially through extended loops (Figure 1). The H protein of MeV forms disulfide-linked dimers on the viral surface that in turn associate to form tetramers [44]. H protein acts in association with F protein to activate fusion during entry and cell-to-cell transmission [13,45]. The fusion activity is associated with conformational changes in F protein that are triggered as H binds to its receptors (reviewed in [46]).

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