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Genomic differences between guinea pig lethal and nonlethal Marburg virus variants
Loreen L Lofts1, M Sofi Ibrahim, Diane L Negley
1Viral Pathogenesis and Immunology Branch, Virology Division, US Army Medical Research Institute for Infectious Diseases, Frederick, MD 21702, USA. loreen.lofts@us.army.mil
Abstract:
The complete genome sequences of 2 closely related plaque-derived variants of Marburg virus (MARV) species Lake Victoria marburgvirus, strain Musoke, indicate only a few regions of the RNA genome as underlying the differences between the 2 viruses. One variant is >90% lethal for guinea pigs and the other much less virulent, when guinea pigs are challenged with 1000 pfu of virus. Only 4 mutations that result in amino acid changes were identified, 1 in viral matrix protein VP40 and 3 in L, the RNA-dependent RNA polymerase. In addition, 6 differences were identified in noncoding regions of transcribed mRNA, and 1 silent codon change was identified in the L gene. Interestingly, the amino acid mutation identified in VP40 occurs in a nonconserved loop structure between 2 domains that are homologues only among MARV species. The L gene mutations were equally intriguing, clustering near a highly conserved motif in viral RNA-dependent RNA polymerases.
Insights
Marburg virus (MARV) genome sequencing revealed few genetic differences between highly lethal and less virulent strains. Key mutations in matrix protein VP40 and RNA-dependent RNA polymerase (L) explain virulence variations.
Area of Science:
- Virology
- Genomics
- Molecular Biology
Background:
- Marburg virus (MARV) causes severe hemorrhagic fever.
- Understanding genetic determinants of MARV virulence is crucial for disease control.
Purpose of the Study:
- To identify genetic differences between two closely related MARV variants with distinct virulence in guinea pigs.
- To pinpoint specific mutations responsible for observed differences in pathogenicity.
Main Methods:
- Whole-genome sequencing of two MARV variants (Lake Victoria marburgvirus, strain Musoke).
- Comparative analysis of coding and noncoding RNA regions.
- Identification of amino acid-altering mutations and silent codon changes.
Main Results:
- Only a few genomic regions differentiated the two MARV variants.
- Four amino acid-changing mutations were found: one in VP40 and three in the L gene.
- Mutations in VP40 occurred in a nonconserved loop, while L gene mutations were near a conserved polymerase motif.
Conclusions:
- Limited genetic variations underlie significant virulence differences in MARV.
- Specific mutations in VP40 and L genes are likely responsible for altered pathogenicity.
- Further research into these specific mutations can inform MARV therapeutics.
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