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


Autoři: Xin-Ni Lim aff001;  Chao Shan aff003;  Jan K. Marzinek aff005;  Hongping Dong aff003;  Thiam Seng Ng aff001;  Justin S. G. Ooi aff001;  Guntur Fibriansah aff001;  Jiaqi Wang aff001;  Chandra S. Verma aff005;  Peter J. Bond aff005;  Pei-Yong Shi aff003;  Shee-mei Lok aff001
Působiště autorů: Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore aff001;  Centre for Bioimaging Sciences, National University of Singapore, Singapore, Singapore aff002;  Novartis Institute for Tropical Diseases, Singapore, Singapore aff003;  Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America aff004;  Bioinformatics Institute, Agency of Science, Technology and Research (A*STAR), Singapore, Singapore aff005;  School of Biological Sciences, Nanyang Technological University, Singapore, Singapore aff006;  Department of Biological Sciences, National University of Singapore, Singapore, Singapore aff007;  Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Texas, United States of America aff008
Vyšlo v časopise: Molecular basis of dengue virus serotype 2 morphological switch from 29°C to 37°C. PLoS Pathog 15(9): e32767. doi:10.1371/journal.ppat.1007996
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1007996

Souhrn

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.

Klíčová slova:

Biology and life sciences – Physiology – Antibodies – Biochemistry – Proteins – Immune system proteins – Protein interactions – Biochemical simulations – Computational biology – Organisms – Viruses – RNA viruses – Flaviviruses – Dengue virus – Microbiology – Medical microbiology – Microbial pathogens – Viral pathogens – Microbial mutation – Medicine and health sciences – Immune physiology – Immunology – Pathology and laboratory medicine – Pathogens – Physical sciences – Physics – Thermodynamics – Thermal stability – Mathematics – Statistics – principal component analysis – Research and analysis methods – Database and informatics methods – Bioinformatics – Sequence analysis – Sequence alignment – Mathematical and statistical techniques – Statistical methods


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