Genomic Appraisal of the Multifactorial Basis for In Vitro Acquisition of Miltefosine Resistance in Leishmania donovani.
Protozoan parasites of the Leishmania donovani complex are the causative agents of visceral leishmaniasis (VL), the most severe form of leishmaniasis, with high rates of mortality if left untreated. Leishmania parasites are transmitted to humans through the bite of infected female sandflies (Diptera: Phlebotominae), and approximately 500,000 new cases of VL are reported each year. In the absence of a safe human vaccine, chemotherapy, along with vector control, is the sole tool with which to fight the disease. Miltefosine (hexadecylphosphatidylcholine [HePC]), an antitumoral drug, is the only successful oral treatment for VL. In the current study, we describe the phenotypic traits of L. donovani clonal lines that have acquired resistance to HePC. We performed whole-genome and RNA sequencing of these resistant lines to provide an inclusive overview of the multifactorial acquisition of experimental HePC resistance, circumventing the challenge of identifying changes in membrane-bound proteins faced by proteomics. This analysis was complemented by assessment of the in vitro infectivity of HePC-resistant parasites. Our work underscores the importance of complementary "omics" to acquire the most comprehensive insight for multifaceted processes, such as HePC resistance.
Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
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P
Vacchina
Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
B
B
Norris-Mullins
Centro de Investigaciones Biológicas (CIB), CSIC, Madrid, Spain.
M A
MA
Abengózar
Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
C G
CG
Viamontes
Genomics and Bioinformatics Core Facility, University of Notre Dame, Notre Dame, Indiana, USA.
J
J
Sarro
Genomics and Bioinformatics Core Facility, University of Notre Dame, Notre Dame, Indiana, USA.
M T
MT
Stephens
Genomics and Bioinformatics Core Facility, University of Notre Dame, Notre Dame, Indiana, USA.
M E
ME
Pfrender
Centro de Investigaciones Biológicas (CIB), CSIC, Madrid, Spain.
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L
Rivas
Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA miguel.morales@nd.edu.
M A
MA
Morales
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004351:Drug Resistance; D005260:Female; D023281:Genomics / Q000379:methods*; D007893:Leishmania donovani / Q000187:drug effects* / Q000235:genetics*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015800:Protozoan Proteins / Q000378:metabolism*; D011576:Psychodidae / Q000469:parasitology
D000981:Antiprotozoal Agents; D015800:Protozoan Proteins; D010767:Phosphorylcholine; C039128:miltefosine