A neutralization site of DA strain of Theiler's murine encephalomyelitis virus important for disease phenotype
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1Department of Neurology, University of Chicago Medical Center, Illinois 60637, USA.
Abstract:
DA strain of TMEV induces a chronic, persistent, demyelinating disease in SJL/J weanling mice, while inoculation with GDVII strain of TMEV induces an acute, lethal neurovirulent disease. We show that three amino acids in the DA EF loop-DAV P2 141 Lys, 143 Gly, and 173 Thr-are part of a neutralization site of DA monoclonal antibody (mAb), DAmAb1. DA virus with a mutation of VP2 143 from Gly to Asp, like wild-type virus, persists 6 weeks postinfection (PI) and produces white matter disease. DA virus with a mutation of VP2 141 from Lys to Asn persists but does not induce significant white matter disease. DA virus with a mutation of DA VP2 173 from Thr to Phe fails to persist or to induce significant white matter disease. The diversity and complexity of the mutant virus-induced disease phenotype presumably reflects the varied effects of the mutated amino acid residues on the three-dimensional structure of the viral capsid. The localization of DA VP2 141 and VP2 173 near the putative receptor binding region of the virus suggest that a disruption of interactions between the virus and its receptor is important in the late demyelinating disease and for virus neutralization.
Insights
Specific mutations in the Theiler's murine encephalitis virus (TMEV) VP2 protein affect its persistence and ability to cause demyelinating disease in mice. These changes impact viral capsid structure and receptor interactions, influencing disease outcome and antibody neutralization.
Area of Science:
- Virology
- Neuroimmunology
- Structural Biology
Background:
- Theiler's murine encephalitis virus (TMEV) causes distinct diseases: DA strain induces chronic demyelination, while GDVII strain causes acute lethal neurovirulence.
- Understanding TMEV pathogenesis is crucial for developing strategies against persistent viral infections and autoimmune diseases.
Purpose of the Study:
- To investigate the role of specific amino acid residues in the TMEV VP2 protein, particularly in the EF loop, on viral persistence, disease induction, and antibody neutralization.
- To elucidate the structural and functional consequences of mutations within the TMEV capsid.
Main Methods:
- Site-directed mutagenesis of TMEV VP2 gene to alter specific amino acids (VP2 141, 143, 173).
- Inoculation of mutant viruses into SJL/J mice to assess viral persistence and disease phenotype (demyelination).
- Analysis of viral capsid structure and potential receptor interactions.
Main Results:
- Mutation of VP2 143 (Gly to Asp) allowed viral persistence and white matter disease, similar to wild-type DA virus.
- Mutation of VP2 141 (Lys to Asn) resulted in viral persistence but significantly reduced white matter disease.
- Mutation of VP2 173 (Thr to Phe) abrogated viral persistence and disease induction.
Conclusions:
- Specific amino acids in the TMEV VP2 EF loop are critical for viral persistence and the induction of chronic demyelinating disease.
- Mutations affecting these residues alter viral capsid structure, influencing interactions with cellular receptors and antibody binding sites.
- Understanding these structure-function relationships provides insights into TMEV pathogenesis and viral neutralization mechanisms.