A pre-vaccination immune metabolic interplay determines the protective antibody response to a dengue virus vaccine
Adam-Nicolas Pelletier,
Gabriela Pacheco Sanchez,
Abdullah Izmirly,
Mark Watson,
Tiziana Di Pucchio,
Karina Inacio Carvalho,
Abdelali Filali-Mouhim,
Eustache Paramithiotis,
Maria do Carmo S.T. Timenetsky,
Alexander Roberto Precioso,
Jorge Kalil,
Michael S. Diamond,
Elias K. Haddad,
Esper G. Kallas,
Rafick Pierre Sekaly
Affiliations
Adam-Nicolas Pelletier
RPM Bioinfo Solutions, Sainte-Thérèse, QC, Canada; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
Gabriela Pacheco Sanchez
Pathology Advanced Translational Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
Abdullah Izmirly
Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
Mark Watson
CellCarta, Montreal, QC, Canada
Tiziana Di Pucchio
Pathology Advanced Translational Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
Karina Inacio Carvalho
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
Abdelali Filali-Mouhim
Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
Eustache Paramithiotis
CellCarta, Montreal, QC, Canada
Maria do Carmo S.T. Timenetsky
Instituto Adolfo Lutz, São Paulo, Brazil
Alexander Roberto Precioso
Instituto Butantan, São Paulo, Brazil
Jorge Kalil
Laboratory of Immunology, Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil; Institute for Investigation in Immunology-Instituto Nacional de Ciência e Tecnologia-iii-INCT, São Paulo, SP, Brazil
Michael S. Diamond
Departments of Medicine, Molecular Microbiology, and Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Elias K. Haddad
Department of Medicine and Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
Esper G. Kallas
Instituto Butantan, São Paulo, Brazil; Department of Infectious and Parasitic Diseases, Hospital das Clínicas, School of Medicine, University of Sao Paulo, São Paulo 01246-903, Brazil
Rafick Pierre Sekaly
Pathology Advanced Translational Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Corresponding author
Summary: Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways, including TGF-β signaling expressed by CD68low monocytes, and the metabolites phosphatidylcholine (PC) and phosphatidylethanolamine (PE) positively correlate with broadly neutralizing antibody responses against DENV. In contrast, expression of pro-inflammatory pathways and cytokines (IFN and IL-1) in CD68hi monocytes and primary and secondary bile acids negatively correlates with broad DENV-specific antibody responses. Induction of TGF-β and IFNs is done respectively by PC/PE and bile acids in CD68low and CD68hi monocytes. The inhibition of viral sensing by PC/PE-induced TGF-β is confirmed in vitro. Our studies show that the balance between metabolites and the pro- or anti-inflammatory state of innate immune cells drives broad and protective B cell response to a live attenuated dengue vaccine.
