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Sindbis virus mutations which coordinately affect glycoprotein processing, penetration, and virulence in mice
D L Russell1, J M Dalrymple, R E Johnston
1Department of Microbiology, North Carolina State University, Raleigh 27695-7615.
Journal of Virology
|April 1, 1989
Summary
Researchers identified Sindbis virus mutants with altered virulence. A mutation in the E2 glycoprotein affected viral pathogenesis and antibody neutralization, offering insights into Sindbis virus disease.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Sindbis virus (SINV) causes various diseases in humans and animals.
- The S.A.AR86 strain of SINV is virulent in both adult and neonatal mice.
- Understanding viral pathogenesis is crucial for developing effective treatments and vaccines.
Purpose of the Study:
- To isolate and characterize Sindbis virus mutants with altered virulence.
- To investigate the genetic basis of Sindbis virus pathogenesis.
- To identify specific viral proteins involved in virulence and host immune response.
Main Methods:
- Isolation of Sindbis virus mutants using baby hamster kidney cell penetration as a selective pressure.
- Virulence assays in adult and neonatal mice via intracerebral and subcutaneous inoculation.
- Sequence analysis of glycoprotein genes (E1, E2) to identify mutations.
- Assessment of viral particle release and E2 precursor protein (PE2) presence.
- Monoclonal antibody binding assays (R6, R13) and neutralization studies.
Main Results:
- Two classes of Sindbis virus mutants with distinct virulence phenotypes were identified.
- Class I mutants, with a serine-to-asparagine change at E2 glycoprotein position 1, exhibited attenuated virulence in both adult and neonatal mice.
- This mutation created a novel N-linked glycosylation site, altered virion composition (PE2 instead of E2), and abolished binding to specific monoclonal antibodies.
- Class II mutants, with an arginine-for-serine substitution at E2 glycoprotein position 114, showed reduced virulence in neonates (subcutaneous) but retained virulence in adults and neonates (intracerebral).
- Class II mutants had reduced reactivity with monoclonal antibodies R6 and R13 and were more susceptible to neutralization by these antibodies.
Conclusions:
- Mutations in the Sindbis virus E2 glycoprotein significantly impact viral virulence and host-specific pathogenesis.
- Alterations in E2 glycosylation and structure affect viral interactions with host immune factors, including monoclonal antibodies.
- The study provides valuable insights into the molecular mechanisms underlying Sindbis virus virulence and potential targets for therapeutic intervention.