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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Previous studies demonstrated that Leptospira biflexa, a saprophytic species, triggers innate immune responses in the host during early infection. This raised the question of whether these responses could suppress a subsequent challenge with pathogenic Leptospira. We inoculated C3H/HeJ mice with a single or a double dose of L. biflexa before challenge with a pathogenic serovar, Leptospira interrogans serovar Copenhageni FioCruz (LIC). Pre-challenge exposure to L. biflexa did not prevent LIC dissemination and colonization of the kidney. However, it rescued weight loss and mouse survival thereby mitigating disease severity. Unexpectedly, there was correlation between rescue of overall health (weight gain, higher survival, lower kidney fibrosis marker ColA1) and higher shedding of LIC in urine. This stood in contrast to the L. biflexa unexposed LIC challenged control. Immune responses were dominated by increased frequency of effector T helper (CD4+) cells in spleen, as well as significant increases in serologic IgG2a. Our findings suggest that exposure to live saprophytic Leptospira primes the host to develop Th1 biased immune responses that prevent severe disease induced by a subsequent challenge with a pathogenic species. Thus, mice exposed to live saprophytic Leptospira before facing a pathogenic serovar may withstand infection with far better outcomes. Furthermore, a status of homeostasis may have been reached after kidney colonization that helps LIC complete its enzootic cycle.
