Integrative metabolomics and transcriptomics signatures of clinical tolerance to Plasmodium vivax reveal activation of innate cell immunity and T cell signaling

• Type of Material: Article
• Authors: Luiz G. Gardinassi, Emory University; Myriam Arévalo-Herrera, Malaria Vaccine and Drug Development Center; Sócrates Herrera, Malaria Vaccine and Drug Development Center; Regina J. Cordy, Emory University; ViLinh Tran, Emory University; Matthew R. Smith, Emory University; Michelle S. Johnson, University of Alabama; Balu Chacko, University of Alabama; Ken H. Liu, Emory University; Victor M. Darley-Usmar, University of Alabama; Young-Mi Go, Emory University; Dean P Jones, Emory University; Mary R Galinski, Emory University; Shuzhao Li, Emory University
• Language: English
• Date: 2018-04-11
• Publisher: Elsevier: Creative Commons
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.redox.2018.04.011
• Title of Journal or Parent Work: Redox Biology
• ISSN: 2213-2317
• Volume: 17
• Start Page: 158
• End Page: 170
• Grant/Funding Information: This project has been funded in part with federal funds from the National Institutes of Health, Department of Health and Human Services, USA (Contract HHSN272201200031C, Grants R01HL086488, S10OD18006, UH2AI132345 and P30AG050886) UAB Nathan Shock Center, Department of Health and Human Services, USA.
• Keywords: Malaria; Plasmodium vivax; Metabolomics; Integration; Tolerance; Transcriptomics; Platelets; Immunity
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

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.