Resistance of Leishmania (Viannia) Panamensis to Meglumine Antimoniate or Miltefosine Modulates Neutrophil Effector Functions

• Published in: Frontiers in immunology Vol. 9; p. 3040
• Main Authors: Regli, Ivo B, Fernández, Olga Lucía, Martínez-Salazar, Berenice, Gómez, Maria Adelaida, Saravia, Nancy Gore, Tacchini-Cottier, Fabienne
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 21.12.2018
• Subjects: Animals; antimony; Antiprotozoal Agents - pharmacology; Antiprotozoal Agents - therapeutic use; Cells, Cultured; drug resistance; Drug Resistance - immunology; Extracellular Traps - immunology; Extracellular Traps - metabolism; Extracellular Traps - parasitology; Humans; Immunology; Leishmania; Leishmania guyanensis - drug effects; Leishmania guyanensis - immunology; Leishmania guyanensis - isolation & purification; Leishmaniasis, Cutaneous - blood; Leishmaniasis, Cutaneous - drug therapy; Leishmaniasis, Cutaneous - immunology; Leishmaniasis, Cutaneous - parasitology; Meglumine Antimoniate - pharmacology; Meglumine Antimoniate - therapeutic use; Mice; Mice, Inbred C57BL; miltefosine; NETs; neutrophils; Neutrophils - immunology; Neutrophils - metabolism; Neutrophils - parasitology; Parasitic Sensitivity Tests; Phosphorylcholine - analogs & derivatives; Phosphorylcholine - pharmacology; Phosphorylcholine - therapeutic use; Primary Cell Culture; Reactive Oxygen Species - immunology; Reactive Oxygen Species - metabolism; NETs; antimony; drug resistance; miltefosine; neutrophils; Leishmania
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2018.03040

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 . 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 has not been examined. In this study, human and murine neutrophils were infected with MA or MIL drug-resistant . lines derived from a parental . 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 . transfected with a luciferase reporter. We show here that MA and MIL-resistant . lines elicited significantly increased NET formation and MA-resistant . 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- drugs.