title: Leishmania donovani depletes labile iron pool to exploit iron uptake capacity of macrophage for its intracellular growth.
abstract: Intracellular pathogens employ several strategies for iron acquisition from host macrophages for survival and growth, whereas macrophage resists infection by actively sequestering iron. Here, we show that instead of allowing macrophage to sequester iron, protozoan parasite Leishmania donovani (LD) uses a novel strategy to manipulate iron uptake mechanisms of the host and utilizes the taken up iron for its intracellular growth. To do so, intracellular LD directly scavenges iron from labile iron pool of macrophages. Depleted labile iron pool activates iron sensors iron-regulatory proteins IRP1 and IRP2. IRPs then bind to iron-responsive elements present in the 3' UTR of iron uptake gene transferrin receptor 1 by a post-transcriptional mRNA stability mechanism. Increased iron-responsive element-IRP interaction and transferrin receptor 1 expressions in spleen-derived macrophages from LD-infected mice confirm that LD employs similar mechanism to acquire iron during infection into mammalian hosts. Increased intracellular LD growth by holo-transferrin supplementation and inhibited growth by iron chelator treatment confirm the significance of this modulated iron uptake pathway of host in favour of the parasite.
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110 067, India.
authors.forename: Nupur Kanti
authors.initials: NK
authors.lastname: Das
authors.forename: Sudipta
authors.initials: S
authors.lastname: Biswas
authors.forename: Sunil
authors.initials: S
authors.lastname: Solanki
authors.forename: Chinmay K
authors.initials: CK
authors.lastname: Mukhopadhyay
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D005260:Female; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000378:metabolism; D007893:Leishmania donovani / Q000254:growth & development* / Q000378:metabolism*; D008264:Macrophages / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2