A single mutation in the envelope protein modulates flavivirus antigenicity, stability, and pathogenesis
Leslie Goo1, Laura A VanBlargan2, Kimberly A Dowd1
1Viral Pathogenesis Section, National Institutes of Health, Bethesda, MD, United States of America.
Plos Pathogens
|February 17, 2017
Summary
A single mutation in West Nile virus (WNV) envelope (E) protein alters virus breathing, increasing antibody sensitivity and reducing stability. This WNV E protein T198F mutation also showed in vivo attenuation in mice.
Area of Science:
- Virology
- Structural Biology
- Molecular Biology
Background:
- Flavivirus envelope (E) protein exhibits structural flexibility ('breathing'), allowing virions to adopt various conformations.
- The molecular underpinnings and functional impact of these viral conformational dynamics remain largely unexplored.
Purpose of the Study:
- To investigate the molecular basis of flavivirus 'breathing' and its functional consequences.
- To identify specific mutations affecting E protein dynamics and their impact on virus infectivity and stability.
Main Methods:
- Site-directed mutagenesis was used to introduce mutations in the West Nile virus (WNV) E protein hinge region (T198F).
- Neutralization assays with monoclonal antibodies were performed to assess antibody binding and virus infectivity.
- Virus stability assays in solution at physiological temperatures were conducted.
- In vitro growth kinetics and in vivo infection studies in mice were utilized to evaluate viral fitness.
Main Results:
- A T198F mutation in the WNV E protein hinge significantly increased sensitivity (~70-fold) to neutralization by a specific monoclonal antibody.
- This mutation led to increased exposure of a cryptic fusion loop epitope and decreased virus stability in solution.
- Analogous mutations in dengue virus (DENV) and Zika virus (ZIKV) E proteins showed context-dependent effects on epitope accessibility and stability.
- The WNV T198F mutation resulted in attenuated WNV infection in a mouse model, despite similar in vitro growth kinetics.
Conclusions:
- A single mutation at residue 198 of the WNV E protein modulates virus 'breathing', impacting conformational dynamics.
- Modulation of flavivirus breathing influences the accessibility of cryptic epitopes and virus stability.
- The identified mutation provides insights into the structure-function relationships of flavivirus E proteins and their in vitro/in vivo behavior.
Related Concept Videos
02:28Leaky Scanning
5.8K
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.8K
00:36Viral Mutations
40.3K
A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
40.3K
00:56Viral Structure
75.4K
Viruses are extraordinarily diverse in shape and size, but they all have several structural features in common. All viruses have a core that contains a DNA- or RNA-based genome. The core is surrounded by a protective coat of proteins called the capsid. The capsid is composed of subunits called capsomeres. The capsid and genome-containing core are together known as the nucleocapsid.
75.4K