L Van Bockstal3; J Sadlova1; H Aslan3; S Hendrickx3; C Meneses2; S Kamhawi2; P Volf1; L Maes3; G Caljon3;
1 Department of Parasitology, Charles University, Prague, Czech Republic; 2 Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States; 3 Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Belgium
DiscussionINTRODUCTION:Visceral leishmaniasis (VL) is a lethal neglected tropical disease caused by Leishmania donovani and Leishmania infantum. It is a vector-borne disease transmitted by the bites of infected female phlebotomine sand flies. Oral miltefosine (MIL) is used to treat VL, but is increasingly failing. To gain insight into the propagation of miltefosine resistance in VL, this study explored development of resistant parasites with a defective miltefosine transporter (MT) in sand flies.
METHODOLOGY: Infectivity, colonization of stomodeal valve and metacyclogenesis of a MIL-resistant (MIL-R) Leishmania infantum LEM3323 line with a defective MT were assessed in the natural sand fly vectors Phlebotomus perniciosus and Lutzomyia longipalpis. Given our recent description of partial drug dependency of the MT-deficient line, the impact of MIL pre-exposure on sand fly infectivity was explored as well.
RESULTS: A significant reduction in sand fly infection (3-fold), stomodeal valve colonization (7-fold) and differentiation into metacyclics (2-fold) was observed for MIL-R as compared to the isogenic parent MIL-susceptible line in both vectors. Re-introduction of the wildtype MT gene into MIL-R partially restored these parameters. Pre-exposure to MIL did not significantly alter the infectivity of the MIL-R line.
CONCLUSIONS: A defect in the inward translocation machinery through inactivation of the MT protein does not only cause MIL resistance but also negatively impacts L. infantum development and transmissibility potential in its natural sand fly vector.