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Measles viruses with altered envelope protein cytoplasmic tails gain cell fusion competence
T Cathomen1, H Y Naim, R Cattaneo
1Institut für Molekularbiologie, Universität Zürich, Hönggerberg, Switzerland.
Abstract:
The cytoplasmic tail of the measles virus (MV) fusion (F) protein is often altered in viruses which spread through the brain of patients suffering from subacute sclerosing panencephalitis (SSPE). We transferred the coding regions of F tails from SSPE viruses in an MV genomic cDNA. Similarly, we constructed and transferred mutated tail-encoding regions of the other viral glycoprotein hemagglutinin (H) gene. From the mutated genomic cDNAs, we achieved rescue of viruses that harbor different alterations of the F tail, deletions in the membrane-distal half of the H tail, and combinations of these mutations. Viruses with alterations in any of the tails spread rapidly through the monolayer via enhanced cell-cell fusion. Double-tail mutants had even higher fusion competence but slightly decreased infectivity. Analysis of the protein composition of released mutant viral particles indicated that the tails are necessary for accurate virus envelope assembly and suggested a direct F tail-matrix (M) protein interaction. Since even tail-altered glycoproteins colocalized with M protein in intracellular patches, additional interactions may exist. We conclude that in MV infections, including SSPE, the glycoprotein tails are involved not only in virus envelope assembly but also in the control of virus-induced cell fusion.
Insights
Altered measles virus (MV) glycoprotein tails enhance cell-cell fusion and virus spread, impacting subacute sclerosing panencephalitis (SSPE) pathogenesis. These tail modifications are crucial for virus envelope assembly and fusion control.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Measles virus (MV) infection can lead to subacute sclerosing panencephalitis (SSPE), a severe neurological disease.
- Alterations in the cytoplasmic tails of MV glycoproteins, specifically the fusion (F) and hemagglutinin (H) proteins, are observed in SSPE viruses.
Purpose of the Study:
- To investigate the role of MV glycoprotein cytoplasmic tails in viral spread and assembly.
- To determine the impact of specific F and H tail mutations on viral infectivity and cell-cell fusion.
Main Methods:
- Engineered MV genomic cDNA with mutations in the F and H protein cytoplasmic tail-encoding regions.
- Rescued mutant MV strains harboring defined tail alterations.
- Analyzed viral particle composition, cell-cell fusion efficiency, and infectivity of rescued viruses.
Main Results:
- Mutant viruses with altered F or H tails exhibited enhanced cell-cell fusion and rapid spread in cell culture.
- Viruses with combined F and H tail mutations showed even greater fusion competence but reduced infectivity.
- Analysis revealed the necessity of glycoprotein tails for proper virus envelope assembly, suggesting interactions with the matrix (M) protein.
Conclusions:
- MV glycoprotein tails are critical for efficient virus envelope assembly.
- These tails play a significant role in regulating MV-induced cell-cell fusion.
- Tail modifications influence MV pathogenesis, potentially relevant to SSPE development.