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

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. Leishmaniases, a group of diseases caused by a parasite, Leishmania, belong to the most neglected tropical diseases: they are mainly found in low-income countries and affect the poorest populations. These parasites infect cells of the immune system called macrophages, which can kill the intracellular parasites when they receive the right signals from other cells of the immune system, the lymphocytes. 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. Here, we show that the levels of an enzyme, arginase, are significantly increased in the blood of patients with visceral leishmaniasis, but decrease to the same levels as those of healthy controls following successful treatment. Arginase has the capacity to deplete an amino acid, L-arginine, which is crucial for the activation of lymphocytes. Indeed, our results show that the levels of this amino acid are considerably decreased in patients with visceral leishmaniasis. Our results suggest that during the active phase of visceral leishmaniasis, increased arginase results in the depletion of L-arginine, which is responsible for the incapacity of lymphocytes to send the adequate signals to the macrophages.