1. Iron trafficking in patients with Indian Post kala-azar dermal leishmaniasis.
- Author
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Dighal, Aishwarya, Mukhopadhyay, Debanjan, Sengupta, Ritika, Moulik, Srija, Mukherjee, Shibabrata, Roy, Susmita, Chaudhuri, Surya Jyati, Das, Nilay K., and Chatterjee, Mitali
- Subjects
LEISHMANIA mexicana ,CD14 antigen ,VISCERAL leishmaniasis ,TRANSFERRIN receptors ,LEISHMANIA donovani ,INTRACELLULAR pathogens ,PRUSSIAN blue - Abstract
Background: During infections involving intracellular pathogens, iron performs a double-edged function by providing the pathogen with nutrients, but also boosts the host's antimicrobial arsenal. Although the role of iron has been described in visceral leishmaniasis, information regarding its status in the dermal sequel, Post Kala-azar Dermal Leishmaniasis (PKDL) remains limited. Accordingly, this study aimed to establish the status of iron within monocytes/macrophages of PKDL cases. Methodology/Principal findings: The intramonocytic labile iron pool (LIP), status of CD163 (hemoglobin-haptoglobin scavenging receptor) and CD71 (transferrin receptor, Tfr) were evaluated within CD14
+ monocytes by flow cytometry, and soluble CD163 by ELISA. At the lesional sites, Fe3+ status was evaluated by Prussian blue staining, parasite load by qPCR, while the mRNA expression of Tfr (TfR1/CD71), CD163, divalent metal transporter-1 (DMT-1), Lipocalin-2 (Lcn-2), Heme-oxygenase-1 (HO-1), Ferritin, Natural resistance-associated macrophage protein (NRAMP-1) and Ferroportin (Fpn-1) was evaluated by droplet digital PCR. Circulating monocytes demonstrated elevated levels of CD71, CD163 and soluble CD163, which corroborated with an enhanced lesional mRNA expression of TfR, CD163, DMT1 and Lcn-2. Additionally, the LIP was raised along with an elevated mRNA expression of ferritin and HO-1, as also iron exporters NRAMP-1 and Fpn-1. Conclusions/Significance: In monocytes/macrophages of PKDL cases, enhancement of the iron influx gateways (TfR, CD163, DMT-1 and Lcn-2) possibly accounted for the enhanced LIP. However, enhancement of the iron exporters (NRAMP-1 and Fpn-1) defied the classical Ferritinlow /Ferroportinhigh phenotype of alternatively activated macrophages. The creation of such a pro-parasitic environment suggests incorporation of chemotherapeutic strategies wherein the availability of iron to the parasite can be restricted. Author summary: Post kala-azar dermal leishmaniasis (PKDL), a dermal sequel of Visceral Leishmaniasis (VL) is caused by the digenetic protozoan parasite Leishmania donovani. The parasite infects humans and replicates intracellularly within macrophages, cells normally engaged in protecting the host from pathogens. Iron plays a crucial role in microbes and mammalian cells, being needed by the former for its growth and survival, while the latter uses it for activation of the immune system by facilitating generation of reactive oxygen species. Therefore, the availability of iron needs to be tightly regulated to ensure its accessibility for core biological functions, and yet prevent its utilization by intracellular pathogens. Here we investigated the status of intra-macrophage iron along with expression of its transporters in patients with PKDL. Our study suggests that within monocytes/macrophages there is an enhanced entry of iron via the upregulation of CD71 and CD163 that translates into an enhanced labile iron pool and Ferritin. However, the concomitant increase in expression of iron exporters NRAMP-1 and Fpn-1 suggested the host's attempt to deny the pathogen access to iron. This Ferritinhigh /Ferroportinhigh phenotype was in contrast to the conventional Ferritinlow /Ferroportinhigh phenotype present in alternatively activated M2 macrophages. Taken together, the control of iron homeostasis is one of the contributors in the host-pathogen interplay as it influences the course of an infectious disease by favouring either the mammalian host or the invading pathogen. [ABSTRACT FROM AUTHOR]- Published
- 2020
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