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

doi:10.1016/j.redox.2018.04.011

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.

Highlights

IntroductionP. vivax accounted for 41% of estimated malaria cases reported in 2015 outside the African continent [1]
Infections with Plasmodium vivax constitute a major public health problem worldwide
The integration of metabolomics and transcriptomics revealed significant associations induced by the infection (Fig. 4), and we further validate the platelet activation pathway suggested by the integrative analysis (Fig. 5)

Summary

Introduction

P. vivax accounted for 41% of estimated malaria cases reported in 2015 outside the African continent [1]. P. vivax malaria is characterized by a febrile illness, which may develop into severe symptoms and fatal complications [2]. Controlled human malaria infection (CHMI) trials have become a critically important research tool, and have been used to evaluate the immunization efficacy for P. vivax [5,6,7]. A recent CHMI trial confirmed that previous exposure to P. vivax leads to reduced symptoms such as fever and headache [8]. Antibodies from semi-immune individuals reacted to a larger repertoire of P. vivax antigens before infection [9], this was insufficient to control parasite growth after sporozoite challenge [8]. Symptomatic semi-immune individuals exhibited similar antibody (caption on page) 159

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Conclusion