Azathioprine favourably influences the course of malaria

Diwakar Bobbala,Saisudha Koka,Stephan M Huber,Florian Lang,Corinna Geiger,Michael Föller

doi:10.1186/1475-2875-8-102

Abstract

BackgroundAzathioprine triggers suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and exposure of phosphatidylserine at the erythrocyte surface. Eryptosis may accelerate the clearance of Plasmodium-infected erythrocytes. The present study thus explored whether azathioprine influences eryptosis of Plasmodium-infected erythrocytes, development of parasitaemia and thus the course of malaria.MethodsHuman erythrocytes were infected in vitro with Plasmodium falciparum (P. falciparum) (strain BinH) in the absence and presence of azathioprine (0.001 – 10 μM), parasitaemia determined utilizing Syto16, phosphatidylserine exposure estimated from annexin V-binding and cell volume from forward scatter in FACS analysis. Mice were infected with Plasmodium berghei (P. berghei) ANKA by injecting parasitized murine erythrocytes (1 × 106) intraperitoneally. Where indicated azathioprine (5 mg/kg b.w.) was administered subcutaneously from the eighth day of infection.ResultsIn vitro infection of human erythrocytes with P. falciparum increased annexin V-binding and initially decreased forward scatter, effects significantly augmented by azathioprine. At higher concentrations azathioprine significantly decreased intraerythrocytic DNA/RNA content (≥ 1 μM) and in vitro parasitaemia (≥ 1 μM). Administration of azathioprine significantly decreased the parasitaemia of circulating erythrocytes and increased the survival of P. berghei-infected mice (from 0% to 77% 22 days after infection).ConclusionAzathioprine inhibits intraerythrocytic growth of P. falciparum, enhances suicidal death of infected erythrocytes, decreases parasitaemia and fosters host survival during malaria.

Highlights

Azathioprine triggers suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and exposure of phosphatidylserine at the erythrocyte surface
Eryptosis is characterized by cell membrane scrambling leading to phosphatidylserine exposure at the cell surface [3,4,5,6,7]
The present study explored whether azathioprine accelerates eryptosis of P. falciparum-infected erythrocytes and whether it influences parasitaemia and survival during malaria

Summary

Introduction

Azathioprine triggers suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and exposure of phosphatidylserine at the erythrocyte surface. Eryptosis is characterized by cell membrane scrambling leading to phosphatidylserine exposure at the cell surface [3,4,5,6,7]. Triggers of cell membrane scrambling include increased cytosolic Ca2+ activity [3,5,6,8] and ceramide [9]. Ca2+ may enter erythrocytes through Ca2+-permeable cation channels, which could be activated by osmotic shock, oxidative stress or energy depletion [8,10,11,12]. Plasmodium infection imposes oxidative stress onto host erythrocytes, which activates Ca2+permeable cation channels [16] and, fosters cell membrane scrambling and phosphatidylserine exposure at the erythrocyte surface [17]. As phosphatidylserine-exposing cells are bound to receptors of macrophages [19,20] and phagocytosed [21,22], eryptotic cells are rapidly cleared from circulating blood [23]

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