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A matrix-less measles virus is infectious and elicits extensive cell fusion: consequences for propagation in the
T Cathomen1, B Mrkic, D Spehner
1Institut für Molekularbiologie, Abt. I, Universität Zürich, Hönggerberg, 8093 Zürich, Switzerland.
Abstract:
Measles viruses (MV) can be isolated from the brains of deceased subacute sclerosing panencephalitis patients only in a cell-associated form. These viruses are often defective in the matrix (M) protein and always seem to have an altered fusion protein cytoplasmic tail. We reconstituted a cell-free, infectious M-less MV (MV-DeltaM) from cDNA. In comparison with standard MV, MV-DeltaM was considerably more efficient at inducing cell-to-cell fusion but virus titres were reduced approximately 250-fold. In MV-DeltaM-induced syncytia the ribonucleocapsids and glycoproteins largely lost co-localization, confirming the role of M protein as the virus assembly organizer. Genetically modified mice were inoculated with MV-DeltaM or with another highly fusogenic virus bearing glycoproteins with shortened cytoplasmic tails (MV-Delta(tails)). MV-DeltaM and MV-Delta(tails) lost acute pathogenicity but penetrated more deeply into the brain parenchyma than standard MV. We suggest that enhanced cell fusion may also favour the propagation of mutated, assembly-defective MV in human brains.
Insights
Measles virus (MV) lacking matrix protein (MV-DeltaM) shows increased cell fusion but reduced titers. This assembly-defective MV penetrates the brain more effectively, suggesting a mechanism for persistent measles virus infections in the brain.
Area of Science:
- Virology
- Molecular Biology
- Neuroscience
Background:
- Subacute sclerosing panencephalitis (SSPE) is a fatal neurological complication of measles virus (MV) infection.
- MV isolates from SSPE patients are cell-associated and often defective in matrix (M) protein, with altered fusion (F) protein cytoplasmic tails.
Purpose of the Study:
- To investigate the role of the M protein in MV assembly and pathogenesis.
- To characterize the properties of an M-deficient MV (MV-DeltaM) and its potential role in SSPE.
Main Methods:
- Reconstitution of cell-free, infectious MV-DeltaM from cDNA.
- Comparative analysis of MV-DeltaM and standard MV infectivity, cell-to-cell fusion, and M protein function.
- Inoculation of genetically modified mice with MV-DeltaM and MV-Delta(tails) to assess pathogenicity and brain penetration.
Main Results:
- MV-DeltaM exhibited significantly enhanced cell-to-cell fusion compared to standard MV, but with a ~250-fold reduction in virus titers.
- In MV-DeltaM-induced syncytia, ribonucleocapsids and glycoproteins lost co-localization, confirming M protein's role in virus assembly organization.
- Both MV-DeltaM and MV-Delta(tails) lost acute pathogenicity but showed increased penetration into the brain parenchyma in mice.
Conclusions:
- The M protein is crucial for organizing MV assembly and efficient virion production.
- Enhanced cell fusion, even in assembly-defective MVs, may facilitate deeper brain penetration.
- Mutated, assembly-defective MV strains with enhanced fusogenicity could contribute to persistent measles virus infections in the human brain.