Epitope resurfacing on dengue virus-like particle vaccine preparation to induce broad neutralizing antibody
- National Chung-Hsing University, Taiwan, Republic of China
- Academia Sinica, Taiwan, Republic of China
- Centers for Disease Control and Prevention, United States
- National Cheng Kung University, Taiwan, Republic of China
- Cited 7
- Views 2,370
- Annotations
Abstract
Dengue fever is caused by four different serotypes of dengue virus (DENV) which is the leading cause of worldwide arboviral diseases in humans. Virus-like particles (VLPs) containing flavivirus prM/E proteins have been demonstrated to be a potential vaccine candidate; however, the structure of dengue VLP is poorly understood. Herein VLP derived from DENV serotype-2 were engineered becoming highly matured (mD2VLP) and showed variable size distribution with diameter of ~31nm forming the major population under cryo-electron microscopy examination. Furthermore, mD2VLP particles of 31nm diameter possess a T=1 icosahedral symmetry with a groove located within the E-protein dimers near the 2-fold vertices that exposed highly overlapping, cryptic neutralizing epitopes. Mice vaccinated with mD2VLP generated higher cross-reactive (CR) neutralization antibodies (NtAbs) and were fully protected against all 4 serotypes of DENV. Our results highlight the potential of 'epitope-resurfaced' mature-form D2VLPs in inducing quaternary structure-recognizing broad CR NtAbs to guide future dengue vaccine design.
Article and author information
Author details
Funding
Ministry of Science and Technology, Taiwan (104-2320-B-006-027)
- Shang-Rung Wu
Ministry of Science and Technology, Taiwan (105-2320-B-006-017-MY3)
- Shang-Rung Wu
Ministry of Science and Technology, Taiwan (104-2633-B-005-001)
- Day-Yu Chao
Ministry of Science and Technology, Taiwan (MOST 106-2313-B-005-029)
- Jyung-Hurng Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was carried out in compliance with the guidelines for the care and use of laboratory animals of the National Laboratory Animal Center, Taiwan. The animal use protocol has been reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of National Chung Hsing University (Approval Number: 101-58). All efforts were made to minimize suffering of mice.
Reviewing Editor
- Arup K Chakraborty, Massachusetts Institute of Technology, United States
Publication history
- Received: June 6, 2018
- Accepted: October 18, 2018
- Accepted Manuscript published: October 18, 2018 (version 1)
- Version of Record published: November 13, 2018 (version 2)
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Metrics
-
- 2,370
- Page views
-
- 441
- Downloads
-
- 7
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
Downloads (link to download the article as PDF)
Download citations (links to download the citations from this article in formats compatible with various reference manager tools)
Open citations (links to open the citations from this article in various online reference manager services)
Further reading
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Bacteria of the genus Shigella cause shigellosis, a severe gastrointestinal disease that is a major cause of diarrhea-associated mortality in humans. Mice are highly resistant to Shigella and the lack of a tractable physiological model of shigellosis has impeded our understanding of this important human disease. Here we propose that the differential susceptibility of mice and humans to Shigella is due to mouse-specific activation of the NAIP–NLRC4 inflammasome. We find that NAIP–NLRC4-deficient mice are highly susceptible to oral Shigella infection and recapitulate the clinical features of human shigellosis. Although inflammasomes are generally thought to promote Shigella pathogenesis, we instead demonstrate that intestinal epithelial cell (IEC)-specific NAIP–NLRC4 activity is sufficient to protect mice from shigellosis. In addition to describing a new mouse model of shigellosis, our results suggest that the lack of an inflammasome response in IECs may help explain the susceptibility of humans to shigellosis.
-
- Microbiology and Infectious Disease
The spread of antimicrobial resistance and vaccine escape in the human pathogen Streptococcus pneumoniae can be largely attributed to competence-induced transformation. Here, we studied this process at the single-cell level. We show that within isogenic populations, all cells become naturally competent and bind exogenous DNA. We find that transformation is highly efficient and that the chromosomal location of the integration site or whether the transformed gene is encoded on the leading or lagging strand has limited influence on recombination efficiency. Indeed, we have observed multiple recombination events in single recipients in real-time. However, because of saturation and because a single-stranded donor DNA replaces the original allele, transformation efficiency has an upper threshold of approximately 50% of the population. The fixed mechanism of transformation results in a fail-safe strategy for the population as half of the population generally keeps an intact copy of the original genome.
