scholarly journals Subacute sclerosing panencephalitis virus dominantly interferes with replication of wild-type measles virus in a mixed infection: implication for viral persistence.

1992 ◽  
Vol 66 (4) ◽  
pp. 1891-1898 ◽  
Author(s):  
A Hirano
Keyword(s):  
Mixed Infection ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Viral Persistence ◽  
Wild Type

scholarly journals Cell-to-Cell Measles Virus Spread between Human Neurons Is Dependent on Hemagglutinin and Hyperfusogenic Fusion Protein

2018 ◽  
Vol 92 (6) ◽  
Author(s):  
Yuma Sato ◽  
Shumpei Watanabe ◽  
Yoshinari Fukuda ◽  
Takao Hashiguchi ◽  
Yusuke Yanagi ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Acute Infection ◽  
Syncytium Formation ◽  
Wild Type ◽  
F Protein ◽  
Human Neurons ◽  
A Cell ◽  
Nt2 Neurons

ABSTRACTMeasles virus (MV) usually causes acute infection but in rare cases persists in the brain, resulting in subacute sclerosing panencephalitis (SSPE). Since human neurons, an important target affected in the disease, do not express the known MV receptors (signaling lymphocyte activation molecule [SLAM] and nectin 4), how MV infects neurons and spreads between them is unknown. Recent studies have shown that many virus strains isolated from SSPE patients possess substitutions in the extracellular domain of the fusion (F) protein which confer enhanced fusion activity. Hyperfusogenic viruses with such mutations, unlike the wild-type MV, can induce cell-cell fusion even in SLAM- and nectin 4-negative cells and spread efficiently in human primary neurons and the brains of animal models. We show here that a hyperfusogenic mutant MV, IC323-F(T461I)-EGFP (IC323 with a fusion-enhancing T461I substitution in the F protein and expressing enhanced green fluorescent protein), but not the wild-type MV, spreads in differentiated NT2 cells, a widely used human neuron model. Confocal time-lapse imaging revealed the cell-to-cell spread of IC323-F(T461I)-EGFP between NT2 neurons without syncytium formation. The production of virus particles was strongly suppressed in NT2 neurons, also supporting cell-to-cell viral transmission. The spread of IC323-F(T461I)-EGFP was inhibited by a fusion inhibitor peptide as well as by some but not all of the anti-hemagglutinin antibodies which neutralize SLAM- or nectin-4-dependent MV infection, suggesting the presence of a distinct neuronal receptor. Our results indicate that MV spreads in a cell-to-cell manner between human neurons without causing syncytium formation and that the spread is dependent on the hyperfusogenic F protein, the hemagglutinin, and the putative neuronal receptor for MV.IMPORTANCEMeasles virus (MV), in rare cases, persists in the human central nervous system (CNS) and causes subacute sclerosing panencephalitis (SSPE) several years after acute infection. This neurological complication is almost always fatal, and there is currently no effective treatment for it. Mechanisms by which MV invades the CNS and causes the disease remain to be elucidated. We have previously shown that fusion-enhancing substitutions in the fusion protein of MVs isolated from SSPE patients contribute to MV spread in neurons. In this study, we demonstrate that MV bearing the hyperfusogenic mutant fusion protein spreads between human neurons in a cell-to-cell manner. Spread of the virus was inhibited by a fusion inhibitor peptide and antibodies against the MV hemagglutinin, indicating that both the hemagglutinin and hyperfusogenic fusion protein play important roles in MV spread between human neurons. The findings help us better understand the disease process of SSPE.

scholarly journals CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells

2010 ◽  
Vol 84 (9) ◽  
pp. 4183-4193 ◽  
Author(s):  
Akira Watanabe ◽  
Misako Yoneda ◽  
Fusako Ikeda ◽  
Yuri Terao-Muto ◽  
Hiroki Sato ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Neuronal Cells ◽  
Wild Type ◽  
Cyclophilin B ◽  
Transmembrane Glycoprotein ◽  
Signaling Lymphocytic Activation Molecule ◽  
Entry Receptor ◽  
H Protein

ABSTRACT Measles is a highly contagious human disease caused by measles virus (MeV) and remains the leading cause of death in children, particularly in developing countries. Wild-type MeV preferentially infects lymphocytes by using signaling lymphocytic activation molecule (SLAM), whose expression is restricted to hematopoietic cells, as a receptor. MeV also infects other epithelial and neuronal cells that do not express SLAM and causes pneumonia and diarrhea and, sometimes, serious symptoms such as measles encephalitis and subacute sclerosing panencephalitis. The discrepancy between the tissue tropism of MeV and the distribution of SLAM-positive cells suggests that there are unknown receptors other than SLAM for MeV. Here we identified CD147/EMMPRIN (extracellular matrix metalloproteinase inducer), a transmembrane glycoprotein, which acts as a receptor for MeV on epithelial cells. Furthermore, we found the incorporation of cyclophilin B (CypB), a cellular ligand for CD147, in MeV virions, and showed that inhibition of CypB incorporation significantly attenuated SLAM-independent infection on epithelial cells, while it had no effect on SLAM-dependent infection. To date, MeV infection was considered to be triggered by binding of its hemagglutinin (H) protein and cellular receptors. Our present study, however, indicates that MeV infection also occurs via CD147 and virion-associated CypB, independently of MeV H. Since CD147 is expressed in a variety of cells, including epithelial and neuronal cells, this molecule possibly functions as an entry receptor for MeV in SLAM-negative cells. This is the first report among members of the Mononegavirales that CD147 is used as a virus entry receptor via incorporated CypB in the virions.

scholarly journals Fitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes

2021 ◽  
Vol 118 (18) ◽  
pp. e2026027118
Author(s):  
Satoshi Ikegame ◽  
Takao Hashiguchi ◽  
Chuan-Tien Hung ◽  
Kristina Dobrindt ◽  
Kristen J. Brennand ◽  
...  
Keyword(s):  
Measles Virus ◽  
Fitness Landscape ◽  
Subacute Sclerosing Panencephalitis ◽  
Brain Regions ◽  
Wild Type ◽  
Genomic Context ◽  
Fitness Advantage ◽  
Human Neurons ◽  
Selection Of

Measles virus (MeV) is resurgent and caused >200,000 deaths in 2019. MeV infection can establish a chronic latent infection of the brain that can recrudesce months to years after recovery from the primary infection. Recrudescent MeV leads to fatal subacute sclerosing panencephalitis (SSPE) or measles inclusion body encephalitis (MIBE) as the virus spreads across multiple brain regions. Most clinical isolates of SSPE/MIBE strains show mutations in the fusion (F) gene that result in a hyperfusogenic phenotype in vitro and allow for efficient spread in primary human neurons. Wild-type MeV receptor-binding protein is indispensable for manifesting these mutant F phenotypes, even though neurons lack canonical MeV receptors (CD150/SLAMF1 or nectin-4). How such hyperfusogenic F mutants are selected and whether they confer a fitness advantage for efficient neuronal spread is unresolved. To better understand the fitness landscape that allows for the selection of such hyperfusogenic F mutants, we conducted a screen of ≥3.1 × 105 MeV-F point mutants in their genomic context. We rescued and amplified our genomic MeV-F mutant libraries in BSR-T7 cells under conditions in which MeV-F-T461I (a known SSPE mutant), but not wild-type MeV, can spread. We recovered known SSPE mutants but also characterized at least 15 hyperfusogenic F mutations with an SSPE phenotype. Structural mapping of these mutants onto the prefusion MeV-F trimer confirm and extend our understanding of the F regulatory domains in MeV-F. Our list of hyperfusogenic F mutants is a valuable resource for future studies into MeV neuropathogenesis and the regulation of paramyxovirus F.

scholarly journals Weak cis and trans Interactions of the Hemagglutinin with Receptors Trigger Fusion Proteins of Neuropathogenic Measles Virus Isolates

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Yuta Shirogane ◽  
Takao Hashiguchi ◽  
Yusuke Yanagi
Keyword(s):  
Membrane Fusion ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Target Cells ◽  
Wild Type ◽  
F Protein ◽  
The Brain ◽  
H Protein ◽  
In Cells ◽  
Cell Cell

ABSTRACT Measles virus (MeV) is an enveloped RNA virus bearing two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. Upon receptor binding, the H protein triggers conformational changes of the F protein, causing membrane fusion and subsequent virus entry. MeV may persist in the brain, infecting neurons and causing fatal subacute sclerosing panencephalitis (SSPE). Since neurons do not express either of the MeV receptors, signaling lymphocytic activation molecule (SLAM; also called CD150) and nectin-4, how MeV propagates in neurons is unknown. Recent studies have shown that specific substitutions in the F protein found in MeV isolates from SSPE patients are critical for MeV neuropathogenicity by rendering the protein unstable and hyperfusogenic. Recombinant MeVs possessing the F proteins with such substitutions can spread in primary human neurons and in the brains of mice and hamsters and induce cell-cell fusion in cells lacking SLAM and nectin-4. Here, we show that receptor-blind mutant H proteins that have decreased binding affinities to receptors can support membrane fusion mediated by hyperfusogenic mutant F proteins, but not the wild-type F protein, in cells expressing the corresponding receptors. The results suggest that weak interactions of the H protein with certain molecules (putative neuron receptors) trigger hyperfusogenic F proteins in SSPE patients. Notably, where cell-cell contacts are ensured, the weak cis interaction of the H protein with SLAM on the same cell surface also could trigger hyperfusogenic F proteins. Some enveloped viruses may exploit such cis interactions with receptors to infect target cells, especially in cell-to-cell transmission. IMPORTANCE Measles virus (MeV) may persist in the brain, causing incurable subacute sclerosing panencephalitis (SSPE). Because neurons, the main target in SSPE, do not express receptors for wild-type (WT) MeV, how MeV propagates in the brain is a key question for the disease. Recent studies have demonstrated that specific substitutions in the MeV fusion (F) protein are critical for neuropathogenicity. Here, we show that weak cis and trans interactions of the MeV attachment protein with receptors that are not sufficient to trigger the WT MeV F protein can trigger the mutant F proteins from neuropathogenic MeV isolates. Our study not only provides an important clue to understand MeV neuropathogenicity but also reveals a novel viral strategy to expand cell tropism.

scholarly journals Measles Virus: Identification in the M Protein Primary Sequence of a Potential Molecular Marker for Subacute Sclerosing Panencephalitis

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Hasan Kweder ◽  
Michelle Ainouze ◽  
Joanna Brunel ◽  
Denis Gerlier ◽  
Evelyne Manet ◽  
...  
Keyword(s):  
Molecular Marker ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
M Protein ◽  
Wild Type ◽  
Virus Identification ◽  
Viral Spread ◽  
M Proteins ◽  
Children And Young Adults ◽  
The Brain

Subacute Sclerosing Panencephalitis (SSPE), a rare lethal disease of children and young adults due to persistence of measles virus (MeV) in the brain, is caused by wild type (wt) MeV. Why MeV vaccine strains never cause SSPE is completely unknown. Hypothesizing that this phenotypic difference could potentially be represented by a molecular marker, we compared glycoprotein and matrix (M) genes from SSPE cases with those from the Moraten vaccine strain, searching for differential structural motifs. We observed that all known SSPE viruses have residues P64, E89, and A209 (PEA) in their M proteins whereas the equivalent residues for vaccine strains are either S64, K89, and T209 (SKT) as in Moraten or PKT. Through the construction of MeV recombinants, we have obtained evidence that the wt MeV-M protein PEA motif, in particular A209, is linked to increased viral spread. Importantly, for the 10 wt genotypes (of 23) that have had their M proteins sequenced, 9 have the PEA motif, the exception being B3, which has PET. Interestingly, cases of SSPE caused by genotype B3 have yet to be reported. In conclusion, our results strongly suggest that the PEA motif is a molecular marker for wt MeV at risk to cause SSPE.

scholarly journals Mutations in the H, F, or M Proteins Can Facilitate Resistance of Measles Virus to Neutralizing Human Anti-MV Sera

2014 ◽  
Vol 2014 ◽  
pp. 1-18 ◽  
Author(s):  
Hasan Kweder ◽  
Michelle Ainouze ◽  
Sara Louise Cosby ◽  
Claude P. Muller ◽  
Camille Lévy ◽  
...  
Keyword(s):  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Laboratory Strain ◽  
Viral Escape ◽  
Wild Type ◽  
Immune Resistance ◽  
M Proteins ◽  
Escape Mutants ◽  
Shed Light

Although there is currently no evidence of emerging strains of measles virus (MV) that can resist neutralization by the anti-MV antibodies present in vaccinees, certain mutations in circulating wt MV strains appear to reduce the efficacy of these antibodies. Moreover, it has been hypothesized that resistance to neutralization by such antibodies could allow MV to persist. In this study, we use a novelin vitrosystem to determine the molecular basis of MV’s resistance to neutralization. We find that both wild-type and laboratory strain MV variants that escape neutralization by anti-MV polyclonal sera possess multiple mutations in their H, F, and M proteins. Cytometric analysis of cells expressing viral escape mutants possessing minimal mutations and their plasmid-expressed H, F, and M proteins indicates that immune resistance is due to particular mutations that can occur in any of these three proteins that affect at distance, rather than directly, the native conformation of the MV-H globular head and hence its epitopes. A high percentage of the escape mutants contain mutations found in cases of Subacute Sclerosing Panencephalitis (SSPE) and our results could potentially shed light on the pathogenesis of this rare fatal disease.

scholarly journals The F Gene of the Osaka-2 Strain of Measles Virus Derived from a Case of Subacute Sclerosing Panencephalitis Is a Major Determinant of Neurovirulence

2010 ◽  
Vol 84 (21) ◽  
pp. 11189-11199 ◽  
Author(s):  
Minoru Ayata ◽  
Kaoru Takeuchi ◽  
Makoto Takeda ◽  
Shinji Ohgimoto ◽  
Seiichi Kato ◽  
...  
Keyword(s):  
Recombinant Virus ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Syncytium Formation ◽  
Vero Cells ◽  
Wild Type ◽  
M Gene ◽  
Hamster Model ◽  
F Protein ◽  
F Gene

ABSTRACT Measles virus (MV) is the causative agent for acute measles and subacute sclerosing panencephalitis (SSPE). Although numerous mutations have been found in the MV genome of SSPE strains, the mutations responsible for the neurovirulence have not been determined. We previously reported that the SSPE Osaka-2 strain but not the wild-type strains of MV induced acute encephalopathy when they were inoculated intracerebrally into 3-week-old hamsters. The recombinant MV system was adapted for the current study to identify the gene(s) responsible for neurovirulence in our hamster model. Recombinant viruses that contained envelope-associated genes from the Osaka-2 strain were generated on the IC323 wild-type MV background. The recombinant virus containing the M gene alone did not induce neurological disease, whereas the H gene partially contributed to neurovirulence. In sharp contrast, the recombinant virus containing the F gene alone induced lethal encephalopathy. This phenotype was related to the ability of the F protein to induce syncytium formation in Vero cells. Further study indicated that a single T461I substitution in the F protein was sufficient to transform the nonneuropathogenic wild-type MV into a lethal virus for hamsters.

scholarly journals Wild-type Measles Virus in Brain Tissue of Children with Subacute Sclerosing Panencephalitis, Argentina

2003 ◽  
Vol 9 (10) ◽  
pp. 1333-1336 ◽  
Author(s):  
Paola Roxana Barrero ◽  
Jorge Grippo ◽  
Mariana Viegas ◽  
Alicia Susana Mistchenko
Keyword(s):  
Brain Tissue ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Wild Type

scholarly journals Fitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes

2020 ◽  
Author(s):  
Satoshi Ikegame ◽  
Takao Hashiguchi ◽  
Chuan-tien Hung ◽  
Kristina Dobrindt ◽  
Kristen Brennand ◽  
...  
Keyword(s):  
Measles Virus ◽  
Fitness Landscape ◽  
Subacute Sclerosing Panencephalitis ◽  
Brain Regions ◽  
Wild Type ◽  
Genomic Context ◽  
Fitness Advantage ◽  
Human Neurons ◽  
Selection Of

Measles virus (MeV) is resurgent and caused >200,000 deaths in 2019. MeV infection can establish a chronic latent infection of the brain that can recrudesce months to years after recovery from the primary infection. Recrudescent MeV leads to fatal subacute sclerosing panencephalitis (SSPE) or measles inclusion body encephalitis (MIBE) as the virus spreads across multiple brain regions. Most clinical isolates of SSPE/MIBE strains show mutations in the fusion (F) gene that result in a hyperfusogenic phenotype in vitro and allow for efficient spread in primary human neurons. Wild-type MeV receptor binding protein (RBP) is indispensable for manifesting these mutant F phenotypes, even though neurons lack canonical MeV receptors (CD150/SLAMF1 or Nectin-4). How such hyperfusogenic F mutants are selected for, and whether they confer a fitness advantage for efficient neuronal spread is unresolved. To better understand the fitness landscape that allows for the selection of such hyperfusogenic F mutants, we conducted a screen of ≥3.1x105 MeV-F point mutants in their genomic context. We rescued and amplified our genomic MeV-F mutant libraries in BSR-T7 cells under conditions where MeV-F-T461I (a known SSPE mutant), but not wild-type MeV can spread. We recovered known SSPE mutants but also characterized at least 15 novel hyperfusogenic F mutations with a SSPE phenotype. Structural mapping of these mutants onto the pre-fusion MeV-F trimer confirm and extend our understanding of the fusion regulatory domains in MeV-F. Our list of hyperfusogenic F mutants is a valuable resource for future studies into MeV neuropathogenesis and the regulation of paramyxovirus fusion.

scholarly journals Comparison of wild-type and subacute sclerosing panencephalitis strains of measles virus. Neurovirulence in ferrets and biological properties in cell cultures.

1978 ◽  
Vol 148 (3) ◽  
pp. 674-691 ◽  
Author(s):  
H Thormar ◽  
P D Mehta ◽  
H R Brown
Keyword(s):  
Cell Fusion ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Biological Properties ◽  
The Other ◽  
Wild Type ◽  
Free Virus ◽  
Other Hand ◽  
The Brain ◽  
Virus Strains

The neurovirulence of two wild type (wt) and seven Subacute Sclerosing Panencephalitis (SSPE) measles virus strains was tested in young adult ferrets by intracerebral (IC) inoculation of infected Vero cell suspensions. Wt strains Edmonston and Woodfolk and SSPE strains Mantooth, Halle, and LEC-S did not produce a detectable encephalitis in the ferrets, but caused a significant formation of serum antibodies against measles virus. SSPE strains LEC, IP-3, Biken, and D.R., on the other hand, were all neurovirulent in ferrets, particularly strain D.R. which caused an acute encephalitis in all inoculated animals. Strain Biken was of particular interest since it caused a subacute encephalitis in four of seven ferrets. The subacute encephalitis was characterized by a long incubation time, persistence of virus in the brain for at least 8 mo, widespread inflammatory lesions, and production of measles virus specific IgG in the brain. A study of the biological properties of the various measles virus strains showed that wt strains Edmonston and Woodfolk and SSPE strains Mantooth, Halle, and LEC-S produced free virus particles in significant titers both in Vero and ferret brain (FB) cultures. Cytopathic effect (CPE) with cell-fusion was marked in Vero cultures, whereas only minimal CPE and no cell-fusion were observed in the FB cultures. SSPE strains LEC, IP-3, Biken, and D.R., on the other hand, were mostly cell-associated in Vero and FB cultures, although atypical cell-free particles were produced by strains Biken and IP-3. All four strains showed cell-fusing activity in FB cultures, particularly strain D.R., which was the only strain that spread more actively by fusion in FB than in Vero cultures. The results are discussed in relation to the neurovirulence of the various measles virus strains in adult ferrets. Pronounced cell-fusing activity in FB cells and cell-association with minimal or no production of cell-free virus seem to be essential to establish a brain infection in the animals.

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