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Generation and properties of measles virus mutations typically associated with subacute sclerosing panencephalitis
M A Billeter1, R Cattaneo, P Spielhofer
1Institut für Molekularbiologie I, Universität Zürich, Switzerland.
Abstract:
Subacute sclerosing panencephalitis (SSPE), a very rare but lethal disease caused by measles viruses (MV) persisting in the human central nervous system (CNS) is characterized by lack of viral budding, reduced expression of the viral envelope proteins and spread of MV genomes through the CNS despite massive immune responses. The five major MV genes from several SSPE cases were cloned and sequenced, the two transmembrane envelope glycoproteins hemagglutinin (H) and fusion protein (F) were expressed and their maturation, cellular localization and functionality analyzed. We conclude that 1) mutations in the MV genes arise not only individually, by errors of the MV polymerase, but also in clusters as hypermutations, presumably due to RNA unwinding/modifying activity altering accidentally formed double-stranded RNA regions, 2) MVs spread in SSPE brains after clonal selection, 3) the MV matrix (M) gene is most heavily mutated and dispensable, 4) the two genes encoding envelope transmembrane proteins give rise to functional but altered proteins (typically F is heavily altered in its cytoplasmic domain), 5) H protein is transported poorly to the cell surface, 6) F and H proteins maintain tightly interdepending fusion functions, presumably to allow local cell fusion and MV ribonucleoprotein (RNP) spread through the CNS.
Insights
Subacute sclerosing panencephalitis (SSPE) involves persistent measles virus (MV) in the CNS. Research reveals MV gene mutations and altered envelope proteins contribute to SSPE pathogenesis and spread.
Area of Science:
- Neuroscience
- Virology
- Genetics
Background:
- Subacute sclerosing panencephalitis (SSPE) is a rare, fatal neurological disease caused by persistent measles virus (MV) in the human central nervous system (CNS).
- SSPE is marked by absent viral budding, diminished viral envelope protein expression, and MV genome dissemination despite strong immune responses.
Purpose of the Study:
- To investigate the genetic mutations and functional alterations of measles virus (MV) genes in subacute sclerosing panencephalitis (SSPE).
- To analyze the maturation, localization, and function of MV envelope glycoproteins (H and F) in SSPE.
Main Methods:
- Cloning and sequencing of five major MV genes from SSPE cases.
- Expression and analysis of MV hemagglutinin (H) and fusion (F) proteins.
Main Results:
- MV genes accumulate mutations individually and in clusters (hypermutations), potentially due to RNA modification activities.
- Measles viruses spread within SSPE brains through clonal selection.
- The MV matrix (M) gene is highly mutated and dispensable.
- Envelope proteins H and F yield functional but altered proteins, with F often showing cytoplasmic domain changes.
- H protein exhibits poor transport to the cell surface.
- F and H proteins maintain interdependent fusion functions, facilitating cell fusion and MV ribonucleoprotein spread.
Conclusions:
- Mutational patterns in MV genes, including hypermutation, are significant in SSPE.
- Altered MV envelope proteins (H and F) play a crucial role in SSPE pathogenesis and viral spread within the CNS.
- The findings elucidate mechanisms of MV persistence and spread in the human CNS during SSPE.