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PLoS Pathog. 2019 Sep 19;15(9):e1007996. doi: 10.1371/journal.ppat.1007996. eCollection 2019 Sep.

Molecular basis of dengue virus serotype 2 morphological switch from 29°C to 37°C.

Lim XN1,2, Shan C3,4, Marzinek JK5, Dong H3, Ng TS1,2, Ooi JSG1,2, Fibriansah G1,2, Wang J1,2, Verma CS5,6,7, Bond PJ5,7, Shi PY3,4,8, Lok SM1,2,7.

Author information

1
Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore.
2
Centre for Bioimaging Sciences, National University of Singapore, Singapore, Singapore.
3
Novartis Institute for Tropical Diseases, Singapore, Singapore.
4
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
5
Bioinformatics Institute, Agency of Science, Technology and Research (A*STAR), Singapore, Singapore.
6
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
7
Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
8
Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Texas, United States of America.

Abstract

The ability of DENV2 to display different morphologies (hence different antigenic properties) complicates vaccine and therapeutics development. Previous studies showed most strains of laboratory adapted DENV2 particles changed from smooth to "bumpy" surfaced morphology when the temperature is switched from 29°C at 37°C. Here we identified five envelope (E) protein residues different between two alternative passage history DENV2 NGC strains exhibiting smooth or bumpy surface morphologies. Several mutations performed on the smooth DENV2 infectious clone destabilized the surface, as observed by cryoEM. Molecular dynamics simulations demonstrated how chemically subtle substitution at various positions destabilized dimeric interactions between E proteins. In contrast, three out of four DENV2 clinical isolates showed a smooth surface morphology at 37°C, and only at high fever temperature (40°C) did they become "bumpy". These results imply vaccines should contain particles representing both morphologies. For prophylactic and therapeutic treatments, this study also informs on which types of antibodies should be used at different stages of an infection, i.e., those that bind to monomeric E proteins on the bumpy surface or across multiple E proteins on the smooth surfaced virus.

PMID:
31536610
PMCID:
PMC6752767
DOI:
10.1371/journal.ppat.1007996
[Indexed for MEDLINE]
Free PMC Article

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