Arginase Activity - A Marker of Disease Status in Patients with Visceral Leishmaniasis in Ethiopia

Tamrat Abebe,Yegnasew Takele,Yifru Sisay,Margaux Corset,Fabienne Tacchini-Cottier,Ellen Closs,Teklu Weldegebreal,Markus Munder,Pascale Kropf,Camille Corset,Workagegnehu Hailu,Ingrid Müller,Tom Cloke,Manuel Modolell,Karina Corware,Asrat Hailu

doi:10.1371/journal.pntd.0002134

Abstract

The underlying mechanisms resulting in the profound immune suppression characteristic of human visceral leishmaniasis (VL) are not fully understood.Here, we tested the hypothesis that arginase, an enzyme associated with immunosuppression, is higher in patients with VL and contributes to impaired T cell responses. We recruited patients with VL before and after treatment and healthy controls and measured the arginase metabolism in the blood of these individuals. Our results show that arginase activity is significantly higher in the blood of patients with active VL as compared to controls. These high levels of arginase decline considerably once the patients are successfully treated. We identified the phenotype of arginase-expressing cells among PBMCs as neutrophils and show that their frequency was increased in PBMCs of patients before treatment; this coincides with reduced levels of L-arginine in the plasma and decreased expression levels of CD3ζ in T cells.

Highlights

Visceral leishmaniasis (VL) is a neglected tropical disease caused by parasites of the Leishmania (L.) donovani complex
During the active phase of visceral leishmaniasis, it has been shown that lymphocytes lose their capacity to instruct the macrophages to kill the intracellular parasites
Our results show that the levels of this amino acid are considerably decreased in patients with visceral leishmaniasis

Summary

Introduction

Visceral leishmaniasis (VL) is a neglected tropical disease caused by parasites of the Leishmania (L.) donovani complex. It inflicts an immense toll on the developing world and impedes economic development; it is the second biggest parasitic killer in the world after malaria, with an estimated loss of 2.3 million disability-adjusted life years. In Ethiopia, VL is caused by L. donovani and it is one of the most significant vector-borne diseases; Ethiopia has the second largest number of VL cases in sub-Saharan Africa with an estimated annual burden of 4500 to 5000 new cases [2]. Sodium stibogluconate (SSG) is still the main drug used as first line of treatment in Ethiopia [2] and a case fatality rate of 13% has been reported [3]. VL is worsened by malnutrition and HIV coinfection, and treatment access is often difficult because of the remote location of areas endemic for VL

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Conclusion