title: Leishmania major CorA-like magnesium transporters play a critical role in parasite development and virulence.
abstract: Establishment of infection by Leishmania depends on the transformation of the invading metacyclic promastigotes into the obligatory intracellular amastigotes, and their subsequent survival in the macrophage phagolysosome, which is low in magnesium. We show that two Leishmania major proteins designated MGT1 and MGT2, which play a critical role in these processes, belong to the two-transmembrane domain (2-TM-GxN) cation transporter family and share homology with the major bacterial magnesium transporter CorA. Although both are present in the endoplasmic reticulum throughout the life cycle of the parasite, MGT1 is more highly expressed in the infectious metacyclic parasites, while MGT2 is enriched in the immature procyclic stages. The two proteins, although predicted to be structurally similar, have features that suggest different regulatory or gating mechanisms. The two proteins may also be functionally distinct, since only MGT1 complements an Escherichia coli DeltaCorA mutant. In addition, deletion of one mgt1 allele from L. major led to increased virulence, while deletion of one allele of mgt2 resulted in slower growth and total loss of virulence in vitro and in vivo. This loss of virulence may be due to an impaired transformation of the parasites into amastigotes. Deletion of both mgt1 alleles in the hemizygous MGT2 knockdown parasites reversed the growth defect and partially restored virulence. Our data indicate that the MGTs play a critical role in parasite growth, development and virulence.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Vic., Australia. yinzhu@unimelb.edu.au
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.forename: Antony
authors.initials: A
authors.lastname: Davis
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Joan
authors.initials: J
authors.lastname: Curtis
authors.forename: Emanuela
authors.initials: E
authors.lastname: Handman
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000737:chemistry; D029968:Escherichia coli Proteins / Q000235:genetics; D017353:Gene Deletion; D005816:Genetic Complementation Test; D018320:Leishmania major / Q000254:growth & development* / Q000472:pathogenicity*; D016773:Leishmaniasis, Cutaneous / Q000469:parasitology; D008264:Macrophages / Q000469:parasitology; D008274:Magnesium / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D027682:Cation Transport Proteins; C514433:CorA protein, E coli; D029968:Escherichia coli Proteins; D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; D037521:Virulence Factors; D008274:Magnesium