Species-Specific Antimonial Sensitivity in Leishmania Is Driven by Post-Transcriptional Regulation of AQP1

Abstract

Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the first line drugs for treating leishmaniasis. Recent studies suggest that pentavalent antimony (Sb(V)) acts as a pro-drug, which is converted to the more active trivalent form (Sb(III)). However, sensitivity to trivalent antimony varies among different Leishmania species. In general, Leishmania species causing cutaneous leishmaniasis (CL) are more sensitive to Sb(III) than the species responsible for visceral leishmaniasis (VL). Leishmania aquaglyceroporin (AQP1) facilitates the adventitious passage of antimonite down a concentration gradient. In this study, we show that Leishmania species causing CL accumulate more antimonite, and therefore exhibit higher sensitivity to antimonials, than the species responsible for VL. This species-specific differential sensitivity to antimonite is directly proportional to the expression levels of AQP1 mRNA. We show that the stability of AQP1 mRNA in different Leishmania species is regulated by their respective 3’-untranslated regions. The differential regulation of AQP1 mRNA explains the distinct antimonial sensitivity of each species.

Effectiveness of Short-Course Meglumine Antimoniate (Glucantime®) for Treatment of Visceral Leishmaniasis: A 13-Year, Multistage, Non-Inferiority Study in Iran

“…1,7 Administration of 20 mg/kg/day Glucantime for 20-30 days leads to a cure rate of about 90% in these regions. 1,8 As for therapeutic regimens, the dosage and duration of treatment vary from country to country, due to the differences in the sensitivity of parasites to antileishmanial compounds.…”

“…6 Among nearly 25 compounds having antileishmanial effects, antimony (sodium antimony gluconate and meglumine antimoniate) has been the therapeutic cornerstone of VL throughout the world for more than 80 years. 1,7 It is still in widespread use with a cure rate of more than 90%, except in the southern Europe and Bihar state of India where low cure rates (36-69%) have been reported. 8,9 The meglumine antimoniate (Glucantime ® ) is recommended to be administered in doses of 20 mg/kg/day (SbV) up to a maximum of 850 mg for 4 weeks by the WHO Expert Committee.…”

Silver and Nitrate Oppositely Modulate Antimony Susceptibility through Aquaglyceroporin 1 in Leishmania (Viannia) Species

“…AQP1-mediated antimony sensitivity is species specific, with cutaneous leishmaniasis-associated species being more sensitive to the drug. This phenotype is a result of posttranscriptionally regulated AQP1 expression (13). Although the molecular basis of the mechanisms of resistance are not fully understood, the downregulation, mutation, and deletion of the AQP1-encoding gene have been clearly associated with Sb resis-tance in both laboratory-selected and field isolates of Leishmania (14)(15)(16).…”

Diagnostic Efficacy of Molecular Techniques for Detection and Identification of Leishmania Species in Human Whole Blood and Skin Samples from Ecuador

“…17 For instance, Leishmania tropica, L. major, Leishmania aethiopica, and L. mexicana complexes cause CL 18 ; disseminated cutaneous leishmaniasis is caused by L. braziliensis, L. amazonensis, and L. guyanensis 19 ; and MCL is usually caused by L. braziliensis 19 and in rare cases by L. panamensis and L. guyanensis. 17 Leishmania species also respond differently to treatment, 17,18,20 for example, species-specific antimonial sensitivity has been determined in an in vitro study, in which L. tropica, L. braziliensis, and L. panamensis were 3, 2.3, and 6 times more resistant than L. major to this drug. 20 Identification of Leishmania species is critical for the diagnosis and treatment of this infection.…”

“…17 Leishmania species also respond differently to treatment, 17,18,20 for example, species-specific antimonial sensitivity has been determined in an in vitro study, in which L. tropica, L. braziliensis, and L. panamensis were 3, 2.3, and 6 times more resistant than L. major to this drug. 20 Identification of Leishmania species is critical for the diagnosis and treatment of this infection. Use of present PCR diagnosis techniques will contribute to improve the clinical management of this parasitic disease as well as to better understand the anthroponotic transmission of the infection.…”