Research Article: Fitness and Phenotypic Characterization of Miltefosine-Resistant Leishmania major

Date Published: July 31, 2015

Publisher: Public Library of Science

Author(s): Kimbra G. Turner, Paola Vacchina, Maricela Robles-Murguia, Mariha Wadsworth, Mary Ann McDowell, Miguel A. Morales, Louis Maes.

Abstract: Trypanosomatid parasites of the genus Leishmania are the causative agents of leishmaniasis, a neglected tropical disease with several clinical manifestations. Leishmania major is the causative agent of cutaneous leishmaniasis (CL), which is largely characterized by ulcerative lesions appearing on the skin. Current treatments of leishmaniasis include pentavalent antimonials and amphotericin B, however, the toxic side effects of these drugs and difficulty with distribution makes these options less than ideal. Miltefosine (MIL) is the first oral treatment available for leishmaniasis. Originally developed for cancer chemotherapy, the mechanism of action of MIL in Leishmania spp. is largely unknown. While treatment with MIL has proven effective, higher tolerance to the drug has been observed, and resistance is easily developed in an in vitro environment. Utilizing stepwise selection we generated MIL-resistant cultures of L. major and characterized the fitness of MIL-resistant L. major. Resistant parasites proliferate at a comparable rate to the wild-type (WT) and exhibit similar apoptotic responses. As expected, MIL-resistant parasites demonstrate decreased susceptibility to MIL, which reduces after the drug is withdrawn from culture. Our data demonstrate metacyclogenesis is elevated in MIL-resistant L. major, albeit these parasites display attenuated in vitro and in vivo virulence and standard survival rates in the natural sandfly vector, indicating that development of experimental resistance to miltefosine does not lead to an increased competitive fitness in L. major.

Partial Text: Leishmaniasis is caused by protozoan parasites of the genus Leishmania, and presents as a variety of clinical manifestations ranging from lesions on the skin to disseminated visceral infections [1]. Cutaneous leishmaniasis (CL) often results in self-resolving lesions, whereas visceral leishmaniasis (VL) is habitually fatal when left untreated. With an annual incidence of 2 million cases and a prevalence of more than 12 million, leishmaniasis is responsible for 70,000 deaths annually [2]. 88 countries have reported infection, resulting in 350 million individuals at risk for infection and an estimated 2.4 million disability-adjusted life years (DALYs) [2]. These statistics are grossly underestimated due to misdiagnosis and insufficient disease surveillance systems.



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