Abstract
Leishmania (Viannia) panamensis (L. (V.) p.) is the main causative agent of cutaneous leishmaniasis in Colombia and is usually treated with either meglumine antimoniate (MA) or miltefosine (MIL). In recent years, there has been increasing evidence of the emergence of drug-resistance against these compounds. Neutrophils are known to play an important role in immunity against Leishmania. These cells are rapidly recruited upon infection and are also present in chronic lesions. However, their involvement in the outcome of infection with drug-resistant Leishmania has not been examined. In this study, human and murine neutrophils were infected in vitro with MA or MIL drug-resistant L. (V.) p. lines derived from a parental L. (V.) p. drug-susceptible strain. Neutrophil effector functions were assessed analyzing the production of reactive oxygen species (ROS), the formation of neutrophil extracellular trap (NET) and the expression of cell surface activation markers. Parasite killing by neutrophils was assessed using L. (V.) p. transfected with a luciferase reporter. We show here that MA and MIL-resistant L. (V.) p. lines elicited significantly increased NET formation and MA-resistant L. (V.) p. induced significantly increased ROS production in both murine and human neutrophils, compared to infections with the parental MIL and MA susceptible strain. Furthermore, neutrophils exposed to drug-resistant lines showed increased activation, as revealed by decreased expression of CD62L and increased expression of CD66b in human neutrophils yet presented higher survival within neutrophils than the drug-susceptible strain. These results provide evidence that parasite drug-susceptibility may influences neutrophil activation and function as well as parasite survival within neutrophils. Further investigaton of the inter-relationship of drug susceptibility and neutrophil effector function should contribute to better understanding of the factors involved in susceptibility to anti-Leishmania drugs.
Highlights
Cutaneous leishmaniasis is an important public health problem affecting 98 countries and territories worldwide
In Colombia, L. (V.) p. is responsible for the majority of reported cases of cutaneous leishmaniasis [2] though L. (V) braziliensis may be more frequent among occupationally exposed military personnel [3]
To investigate the contribution of neutrophils in the intracellular survival of Leishmania during drug exposure, we first investigated whether L. (V.) p. strains susceptible or resistant to meglumine antimoniate (MA) or MIL would induce different phenotype and function in neutrophils
Summary
Cutaneous leishmaniasis is an important public health problem affecting 98 countries and territories worldwide. There has been an increasing number of reports of treatment failure and loss of susceptibility of clinical Leishmania strains to antimonial drugs, and association of resistance in some cases of therapeutic failure in leishmaniasis patients. Neutrophil presence has been reported to positively affect disease outcome in the case of L. braziliensis [25, 34,35,36], L. amazonensis [37] and L. donovani infection [38]. Using both human and mouse neutrophils, we have investigated in vitro the role of these cells in the context of anti-Leishmania drug resistance following L. These differences in the elicitation of neutrophil function and parasite killing may influence antileishmanial drug therapy
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