Broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics
- Chan Zuckerberg Biohub, United States
- Stanford University, United States
- Integral Molecular, Inc, United States
- Fundación Valle del Lili, Colombia
- Fred Hutchinson Cancer Research Center, United States
Abstract
Eliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To define bNAb targets, we characterized 28 antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified J9 and J8, two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies showed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against DENV with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested that J9 and J8 followed divergent somatic hypermutation pathways, and that a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a new epitope that can be exploited for vaccine design.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 4, and 6.
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In vivo molecular signatures of severe dengue infection revealed by viscRNA-SeqNCBI Gene Expression Omnibus, GSE116672.
Article and author information
Author details
Funding
Chan Zuckerberg Biohub
- Natasha D Durham
- Aditi Agrawal
- Eric Waltari
- Fabio Zanini
- Olivia Smith
- Esteban Carabajal
- John E Pak
- Stephen R Quake
- Krista M McCutcheon
- Leslie Goo
Fred Hutchinson Cancer Research Center
- Leslie Goo
National Institutes of Health (HHSN272201400058C)
- Benjamin J Doranz
NSF Graduate Research Fellowship
- Derek Croote
Kou-I Yeh Stanford Graduate Fellowship
- Derek Croote
Catalyst Award from Dr Ralph and Marian Falk Medical Research Trust
- Shirit Einav
Stanford Bio-X Interdisciplinary Initiatives Seed Grants Program
- Shirit Einav
Stanford Advanced Residency Training at Stanford Fellowship Program
- Makeda Robinson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study was approved by the Stanford University Administrative Panel on Human Subjects in Medical Research (Protocol #35460) and the Fundación Valle del Lili Ethics committee in biomedical research (Cali, Colombia). All subjects, their parents, or legal guardians provided written informed consent, and subjects between 6 to 17 years of age and older provided assent.
Copyright
© 2019, Durham et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics
eLife 8:e52384.
https://doi.org/10.7554/eLife.52384
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Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RA−CCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3−CCR7+Helios−CD127−CD8+) and pro-inflam Macs (CD206−CD163−CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163−CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206− pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.
