Integrative metabolomics and transcriptomics signatures of clinical tolerance to Plasmodium vivax reveal activation of innate cell immunity and T cell signaling
Luiz G. Gardinassi,
Myriam Arévalo-Herrera,
Sócrates Herrera,
Regina J. Cordy,
ViLinh Tran,
Matthew R. Smith,
Michelle S. Johnson,
Balu Chacko,
Ken H. Liu,
Victor M. Darley-Usmar,
Young-Mi Go,
Dean P. Jones,
Mary R. Galinski,
Shuzhao Li
Affiliations
Luiz G. Gardinassi
Department of Medicine, School of Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322-1047, USA
Myriam Arévalo-Herrera
Malaria Vaccine and Drug Development Center (MVDC), Cali, Colombia; Faculty of Health, Universidad del Valle, Cali, Colombia
Sócrates Herrera
Malaria Vaccine and Drug Development Center (MVDC), Cali, Colombia; Caucaseco Scientific Research Center, Cali, Colombia
Regina J. Cordy
International Center for Malaria Research, Education and Development, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA
ViLinh Tran
Department of Medicine, School of Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322-1047, USA
Matthew R. Smith
Department of Medicine, School of Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322-1047, USA
Michelle S. Johnson
Department of Pathology and Mitochondrial Medicine Laboratory, University of Alabama at Birmingham, Birmingham, AL, USA
Balu Chacko
Department of Pathology and Mitochondrial Medicine Laboratory, University of Alabama at Birmingham, Birmingham, AL, USA
Ken H. Liu
Department of Medicine, School of Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322-1047, USA
Victor M. Darley-Usmar
Department of Pathology and Mitochondrial Medicine Laboratory, University of Alabama at Birmingham, Birmingham, AL, USA
Young-Mi Go
Department of Medicine, School of Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322-1047, USA
Dean P. Jones
Department of Medicine, School of Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322-1047, USA
Mary R. Galinski
Department of Medicine, School of Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322-1047, USA; International Center for Malaria Research, Education and Development, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA
Shuzhao Li
Department of Medicine, School of Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322-1047, USA; Corresponding author.
Almost invariably, humans become ill during primary infections with malaria parasites which is a pathology associated with oxidative stress and perturbations in metabolism. Importantly, repetitive exposure to Plasmodium results in asymptomatic infections, which is a condition defined as clinical tolerance. Integration of transcriptomics and metabolomics data provides a powerful way to investigate complex disease processes involving oxidative stress, energy metabolism and immune cell activation. We used metabolomics and transcriptomics to investigate the different clinical outcomes in a P. vivax controlled human malaria infection trial. At baseline, the naïve and semi-immune subjects differed in the expression of interferon related genes, neutrophil and B cell signatures that progressed with distinct kinetics after infection. Metabolomics data indicated differences in amino acid pathways and lipid metabolism between the two groups. Top pathways during the course of infection included methionine and cysteine metabolism, fatty acid metabolism and urea cycle. There is also evidence for the activation of lipoxygenase, cyclooxygenase and non-specific lipid peroxidation products in the semi-immune group. The integration of transcriptomics and metabolomics revealed concerted molecular events triggered by the infection, notably involving platelet activation, innate immunity and T cell signaling. Additional experiment confirmed that the metabolites associated with platelet activation genes were indeed enriched in the platelet metabolome. Keywords: Malaria, Plasmodium vivax, Tolerance, Metabolomics, Transcriptomics, Integration, Platelets, Immunity
