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Cell fusion by the envelope glycoproteins of persistent measles viruses which caused lethal human brain disease
1Department of Pathology, Yale University Medical School, New Haven, Connecticut 06510.
Abstract:
Measles virus (MV) rarely induces lethal diseases of the human central nervous system characterized by reduced expression of the viral envelope proteins and by lack of viral budding. The MV envelope contains two integral membrane proteins, termed fusion (F) protein and hemagglutinin (H) protein, and a membrane-associated matrix (M) protein. Previously, analysis of MV genes from autopsy material indicated that the M protein and the F protein intracellular domain are often drastically altered by mutations. Here, we present evidence that truncation of the F protein intracellular domain does not impair fusion function, and we suggest that this alteration interferes with viral budding. Unexpectedly, certain combinations of functional F and H proteins were unable to induce syncytium formation, an observation suggesting that specific F-H protein interactions are required for cell fusion. We also found that three of four H proteins of persistent MVs are defective in intracellular transport, oligosaccharide modification, dimerization, and fusion helper function. Thus, MVs replicating in the brain at the terminal stage of infection are typically defective in M protein and in the two integral membrane proteins. Whereas the M protein appears dispensable altogether, partial preservation of F-protein function and H-protein function seems to be required, presumably to allow local cell fusion. Certain subtle alterations of the F and H proteins may be instrumental for disease development.
Insights
Measles virus (MV) central nervous system diseases involve altered viral proteins. Specific mutations in fusion (F) and hemagglutinin (H) proteins disrupt viral budding and cell fusion, contributing to disease development.
Area of Science:
- Virology
- Neuroscience
- Molecular Biology
Background:
- Measles virus (MV) can cause lethal human central nervous system diseases.
- These diseases are associated with reduced viral envelope protein expression and impaired viral budding.
- Previous studies noted mutations in MV matrix (M) and fusion (F) proteins from autopsy material.
Purpose of the Study:
- To investigate the role of MV envelope protein alterations in disease pathogenesis.
- To determine the impact of F protein intracellular domain truncation on fusion and budding.
- To explore the necessity of specific F-H protein interactions for cell fusion.
Main Methods:
- Analysis of MV envelope proteins (M, F, H) from infected cells and autopsy material.
- Functional assays for viral fusion and syncytium formation.
- Investigation of intracellular transport and modification of H proteins.
Main Results:
- Truncation of the F protein intracellular domain did not impair fusion but interfered with viral budding.
- Specific F-H protein combinations were unable to induce syncytium formation, indicating a need for precise interactions.
- Three out of four H proteins from persistent MVs showed defects in transport, modification, dimerization, and function.
- MVs in the brain at late infection stages typically have defective M, F, and H proteins.
Conclusions:
- While M protein appears dispensable, partial F and H protein functions are likely required for local cell fusion in MV-induced CNS disease.
- Subtle alterations in F and H proteins may play a crucial role in the development of these neurological diseases.
- Understanding these protein-F-H interactions is key to deciphering MV neuropathogenesis.