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Strength of envelope protein interaction modulates cytopathicity of measles virus
Richard K Plemper1, Anthea L Hammond, Denis Gerlier
1Molecular Medicine Program, Mayo Foundation, Rochester, Minnesota 55905, USA. rplempe@emory.edu
Abstract:
To understand the molecular determinants of measles virus (MV) cytopathicity, we have characterized mutant viruses exhibiting a more-extensive cell-to-cell fusion while maintaining efficient replication to high titers. A virus which is modified by the addition of an 8-amino-acid Flag epitope tag at the cytoplasmic tail of its H (for MV hemagglutinin) envelope glycoprotein replicates efficiently, has an increased cytopathicity, possesses a greater infectivity per particle, and has an altered protein composition compared with that of unmodified MV. The mutant phenotype is not specifically linked to the epitope sequence, since an alternatively added HA (for influenza virus-derived hemagglutinin) epitope tag caused similar effects. We demonstrate that both epitope tags weaken the interaction between the H and fusion (F) glycoproteins in virus-infected cells. This reduction in strength of H/F interaction is independent of the presence of the viral matrix (M) protein. Viruses with this less stable complex are more sensitive to neutralization by a soluble octameric form of the CD46 receptor, consistent with their increased fusogenicity. Similar analyses of glycoproteins derived from MV strains with reduced cytopathicities confirm that the strength of H and F glycoprotein interaction is a modulator of viral fusogenicity.
Insights
Altering measles virus (MV) hemagglutinin (H) glycoprotein by adding epitope tags weakens its interaction with the fusion (F) glycoprotein. This modification increases viral fusogenicity and cytopathicity.
Area of Science:
- Virology
- Molecular Biology
- Cell Biology
Background:
- Measles virus (MV) causes significant cytopathicity, but its molecular determinants remain incompletely understood.
- Understanding MV's cell-to-cell fusion mechanisms is crucial for developing effective antiviral strategies.
Purpose of the Study:
- To investigate the role of hemagglutinin (H) and fusion (F) glycoprotein interactions in modulating MV cytopathicity and fusogenicity.
- To characterize mutant MVs with enhanced cell-to-cell fusion and identify the underlying molecular changes.
Main Methods:
- Generation and characterization of MV mutants with epitope tags (Flag or influenza HA) on the H glycoprotein's cytoplasmic tail.
- Analysis of viral replication, infectivity, cytopathicity, and protein composition.
- Assessment of H/F glycoprotein interaction strength and sensitivity to CD46 receptor-mediated neutralization.
Main Results:
- Epitope-tagged MV mutants exhibited increased cytopathicity, infectivity per particle, and fusogenicity.
- The addition of epitope tags weakened the interaction between H and F glycoproteins, independent of the matrix (M) protein.
- Mutant viruses showed increased sensitivity to neutralization by soluble CD46, correlating with enhanced fusogenicity.
Conclusions:
- The strength of the H/F glycoprotein interaction is a key modulator of MV fusogenicity and cytopathicity.
- Weakening this interaction through modifications like epitope tagging enhances viral spread and cell-to-cell fusion.
- These findings provide insights into MV pathogenesis and potential therapeutic targets.