Erythropoietin Levels Increase during Cerebral Malaria and Correlate with Heme, Interleukin-10 and Tumor Necrosis Factor-Alpha in India.

Esther Dalko,Shobhona Sharma,Nicolas Tchitchek,Serge Nataf,Balachandran Ravindran,Fabien Herbert,Sylviane Pied,Bidyut Das,Laurent Pays,Pierre-André Cazenave

doi:10.1371/journal.pone.0158420

Abstract

Cerebral malaria (CM) caused by Plasmodium falciparum parasites often leads to the death of infected patients or to persisting neurological sequelae despite anti-parasitic treatments. Erythropoietin (EPO) was recently suggested as a potential adjunctive treatment for CM. However diverging results were obtained in patients from Sub-Saharan countries infected with P. falciparum. In this study, we measured EPO levels in the plasma of well-defined groups of P. falciparum-infected patients, from the state of Odisha in India, with mild malaria (MM), CM, or severe non-CM (NCM). EPO levels were then correlated with biological parameters, including parasite biomass, heme, tumor necrosis factor (TNF)-α, interleukin (IL)-10, interferon gamma-induced protein (IP)-10, and monocyte chemoattractant protein (MCP)-1 plasma concentrations by Spearman’s rank and multiple correlation analyses. We found a significant increase in EPO levels with malaria severity degree, and more specifically during fatal CM. In addition, EPO levels were also found correlated positively with heme, TNF-α, IL-10, IP-10 and MCP-1 during CM. We also found a significant multivariate correlation between EPO, TNF-α, IL-10, IP-10 MCP-1 and heme, suggesting an association of EPO with a network of immune factors in CM patients. The contradictory levels of circulating EPO reported in CM patients in India when compared to Africa highlights the need for the optimization of adjunctive treatments according to the targeted population.

Highlights

Malaria eradication is a worldwide public health priority
P. falciparum histidine-rich protein-2 (PfHRP-2) levels were shown to be good indicators of total parasite biomass [31], and they were significantly higher in the plasma of NCM and Cerebral malaria (CM) compared to mild malaria (MM) patients (Table 1)
To investigate if EPO levels were associated with a “protective phenotype” against CM in Odisha, EPO levels were determined in the plasma of P. falciparum-infected patients and Endemic controls (EC)

Summary

Introduction

Malaria eradication is a worldwide public health priority. Children and adults still die from this plague every year due to severe disease manifestations. Cerebral malaria (CM) is the deadliest complication, and as reported by the World Health Organization it is most of the time caused by Plasmodium falciparum infections [1]. The pathophysiology of CM is complex and far from being completely understood. It involves brain inflammation triggered by the sequestration of parasitized erythrocytes, cell death and infiltrating immune cells in the central nervous system, as well as the systemic production of pro-inflammatory cytokines [2]. In 18% of the cases, patients die despite receiving anti-parasitic treatment, and surviving patients often suffer from neurological sequelae [2,3]. There is an important need in finding appropriate adjunctive treatments against CM

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Conclusion