Impact of clinically acquired miltefosine resistance by Leishmania infantum on mouse and sand fly infection. (August 2020)

• Record Type: Journal Article
• Authors: Van Bockstal, Lieselotte; Bulté, Dimitri; Hendrickx, Sarah; Sadlova, Jovana; Volf, Petr; Maes, Louis; Caljon, Guy
• Is Part Of: International journal for parasitology. Volume 13(2020)
• Page Start: 16
• Page End: 21
• Publication Date: 2020-08
• Subjects: Visceral leishmaniasis -- Leishmania infantum -- Miltefosine-resistance -- Bioluminescent imaging -- Lutzomyia longipalpis -- Phlebotomus perniciosus -- Fitness; Parasitic diseases -- Chemotherapy -- Periodicals; Drug resistance -- Periodicals; 616.96061
• DOI: 10.1016/j.ijpddr.2020.04.004
• Languages: English
• ISSNs: 2211-3207

Abstract

Abstract: Objectives: This study evaluated the implications of clinically acquired miltefosine resistance (MIL-R) by assessing virulence in mice and sand flies to reveal the potential of MIL-R strains to circulate. Methods: Experimental infections with the MIL-R clinical Leishmania infantum isolate MHOM/FR/2005/LEM5159, having a defect in the LiROS3 subunit of the MIL-transporter, and its syngeneic experimentally reconstituted MIL-S counterpart (LEM5159 LiROS3 ) were performed in BALB/c mice and Lutzomyia longipalpis and Phlebotomus perniciosus sand flies. In mice, the amastigote burdens in liver and spleen were compared microscopically using Giemsa smears and by bioluminescent imaging. During the sand fly infections, the percentage of infected flies, parasite load, colonization of the stomodeal valve and metacyclogenesis were evaluated. The stability of the MIL-R phenotype after sand fly and mouse passage was determined as well. Results: The fitness of the MIL-R strain differed between the mouse and sand fly infection model. In mice, a clear fitness loss was observed compared to the LiROS3 -reconstituted susceptible strain. This defect could be rescued by episomal reconstitution with a wildtype LiROS3 copy. However, this fitness loss was not apparent in the sand fly vector, resulting in metacyclogenesis and efficient colonization of the stomodeal valve. Resistance was stable after passage in both sand fly and mouse. Conclusion: The natural MIL-R strain is significantly hampered in its ability to multiply and cause a typical visceral infection pattern in BALB/c mice. However, this LiROS3-deficient strain efficiently produced mature infections and metacyclic promastigotes in the sand fly vector highlighting the transmission potential of this particular MIL-R clinical Leishmania strain. Graphical abstract: Image 1 Highlights: A clinical MIL-R L. infantum strain displays a loss-of-fitness in the mammalian host. ROS3-deficiency is compatible with efficient transmission by two sand fly species. Resistance is stable after mouse and sand fly passage. Transmission of this clinical MIL-R strain is a risk for immunocompromised patients.