Longitudinal analysis of acute and convalescent B cell responses in a human primary dengue serotype 2 infection modelResearch in context
Usha K. Nivarthi,
Huy A. Tu,
Matthew J. Delacruz,
Jesica Swanstrom,
Bhumi Patel,
Anna P. Durbin,
Stephen S. Whitehead,
Kristen K. Pierce,
Beth D. Kirkpatrick,
Ralph S. Baric,
Ngan Nguyen,
Daniel E. Emerling,
Aravinda M. de Silva,
Sean A. Diehl
Affiliations
Usha K. Nivarthi
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Huy A. Tu
Department of Microbiology and Molecular Genetics, Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA; Cellular, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, VT 05405, USA
Matthew J. Delacruz
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Jesica Swanstrom
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Bhumi Patel
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Anna P. Durbin
Department of International Health, Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Stephen S. Whitehead
Laboratory of Infectious Diseases, NIAID, National Institutes of Health, Bethesda, MD 20892, USA
Kristen K. Pierce
Department of Microbiology and Molecular Genetics, Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
Beth D. Kirkpatrick
Department of Microbiology and Molecular Genetics, Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
Ralph S. Baric
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Ngan Nguyen
Atreca, Inc. Redwood City, California 94063, USA
Daniel E. Emerling
Atreca, Inc. Redwood City, California 94063, USA
Aravinda M. de Silva
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA; Corresponding authors.
Sean A. Diehl
Department of Microbiology and Molecular Genetics, Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA; Corresponding authors.
Background: Acute viral infections induce a rapid and transient increase in antibody-secreting plasmablasts. At convalescence, memory B cells (MBC) and long-lived plasma cells (LLPC) are responsible for long-term humoral immunity. Following an acute viral infection, the specific properties and relationships between antibodies produced by these B cell compartments are poorly understood. Methods: We utilized a controlled human challenge model of primary dengue virus serotype 2 (DENV2) infection to study acute and convalescent B-cell responses. Findings: The level of DENV2 replication was correlated with the magnitude of the plasmablast response. Functional analysis of plasmablast-derived monoclonal antibodies showed that the DENV2-specific response was dominated by cells producing DENV2 serotype-specific antibodies. DENV2-neutralizing antibodies targeted quaternary structure epitopes centered on domain III of the viral envelope protein (EDIII). Functional analysis of MBC and serum antibodies from the same subjects six months post-challenge revealed maintenance of the serotype-specific response in both compartments. The serum response mainly targeted DENV2 serotype-specific epitopes on EDIII. Interpretation: Our data suggest overall functional alignment of DENV2-specific responses from the plasmablast, through the MBC and LLPC compartments following primary DENV2 inflection. These results provide enhanced resolution of the temporal and specificity of the B cell compartment in viral infection and serve as framework for evaluation of B cell responses in challenge models. Funding: This study was supported by the Bill and Melinda Gates Foundation and the National Institutes of Health. Keywords: Dengue, Viral infection, Humoral immunity, Antibody
