Visceral Leishmaniasis Patients Display Altered Composition and Maturity of Neutrophils as well as Impaired Neutrophil Effector Functions.

Endalew Yizengaw,Pascale Kropf,Edward Cruz Cervera,Yegnasew Takele,Fitsumbrhan Tajebe,Asrat Hailu,Bewketu Mengesha,Manuel Modolell,Arega Yeshanew,Ziv Skhedy,Markus Munder,Vanessa Yardley,Ermias Diro,Mulualem Lemma,Gert Van Der Auwera,Getnet Mesfin,Ingrid Müller,Roma Melkamu,Emebet Adem,Muluwork Getahun

doi:10.3389/fimmu.2016.00517

Abstract

Immunologically, active visceral leishmaniasis (VL) is characterized by profound immunosuppression, severe systemic inflammatory responses, and an impaired capacity to control parasite replication. Neutrophils are highly versatile cells, which play a crucial role in the induction as well as the resolution of inflammation, the control of pathogen replication, and the regulation of immune responses. Neutrophil functions have been investigated in human cutaneous leishmaniasis; however, their role in human VL is poorly understood. In the present study we evaluated the activation status and effector functions of neutrophils in patients with active VL and after successful anti-leishmanial treatment. Our results show that neutrophils are highly activated and have degranulated; high levels of arginase, myeloperoxidase, and elastase, all contained in neutrophils’ granules, were found in the plasma of VL patients. In addition, we show that a large proportion of these cells are immature. We also analyzed effector functions of neutrophils that are essential for pathogen clearance and show that neutrophils have an impaired capacity to release neutrophil extracellular traps, produce reactive oxygen species, and phagocytose bacterial particles, but not Leishmania parasites. Our results suggest that impaired effector functions, increased activation, and immaturity of neutrophils play a key role in the pathogenesis of VL.

Highlights

Leishmaniases are caused by a group of vector-borne parasites that represent a major public health problem worldwide, affecting 98 countries [1]
The Median Fluorescence Intensity (MFI) of intracellular arginase and the MFI of CD62L and CD10 were all decreased in neutrophils from visceral leishmaniasis (VL) patients (Figure 1, p = 0.0028, p = 0.0037, and p = 0.0007, respectively); whereas the MFIs of arginase and CD62L did not increase significantly (p > 0.05) following successful treatment of VL patients, CD10 expression was significantly increased
D, a similar percentages of neutrophils (Figure 5C) phagocytosed a similar number of parasites (Figure 5D). These results show that neutrophils isolated from VL patients have an impaired capacity to phagocytose E. coli particles, but not L. donovani parasites

Summary

Introduction

Leishmaniases are caused by a group of vector-borne parasites that represent a major public health problem worldwide, affecting 98 countries [1]. The majority of individuals infected with these parasites will be able to control infection; some will develop symptomatic disease, in which the mortality rate can be as high as 100% in untreated patients. The symptoms include fever, weight loss, severe anemia, hepato- and splenomegaly, and pancytopenia. [3, 4]] This notion was challenged by studies performed in India [5, 6]: using a whole blood assay, the authors showed that CD4+ T cells produce similar levels of IFN-γ that can limit Leishmania parasite replication during active VL. Our recent work performed in Ethiopia showed that whole blood cells produce no or low IFN-γ, suggesting that whole blood cells from VL patients in Ethiopia are hyporesponsive [7]

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Conclusion