Dataset Information

Iron trafficking in patients with Indian Post kala-azar dermal leishmaniasis.

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.

SUBMITTER: Dighal A

PROVIDER: S-EPMC7001907 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Iron trafficking in patients with Indian Post kala-azar dermal leishmaniasis.

Dighal Aishwarya A Mukhopadhyay Debanjan D Sengupta Ritika R Moulik Srija S Mukherjee Shibabrata S Roy Susmita S Chaudhuri Surya Jyati SJ Das Nilay K NK Chatterjee Mitali M

PLoS neglected tropical diseases 20200205 2

<h4>Background</h4>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.<h4>Me ...[more]

PMID: 32023254

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Project description:Post Kala Azar Dermal Leishmaniasis (PKDL) is a non-fatal dermal sequel of Visceral Leishmaniasis (VL), caused by protozoan parasite Leishmania donovani. On the global scenario, PKDL in mainly restricted to distinct zones of South Asia (India, Nepal and Bangladesh) and East Africa, mainly Sudan. In India, the most prominent fatal form of leishmaniasis present is VL, affecting entirely the eastern region of the country. The clinical presentation of VL and PKDL differ substantially; where VL patients suffer from sustained fever, hepatospleenomegaly, weight loss and anemia, PKDL patients manifest dermal lesions in the form of macular, nodular and polymorphic. Although, compared to VL, the mortality rate of PKDL is significantly lower, yet it is observed as a stigmatizing disease that brings a substantial socioeconomic burden, further intensified by a hesitancy of patients, to obtain treatment, or due to noncompliance. Lesions, especially the polymorphic forms, are parasite-rich, concluding that PKDL plays a crucial role in the anthroponotic transmission of VL. PKDL patients with Macular lesions, having comparatively lower parasitic load, and thus lacks detection sensitivity with standard techniques like rK39 (73% sensitivity), Leishmanin skin test (54% sensitivity) and Histopathological studies with patients’ skin biopsy sample (7-33% sensitivity) and is often misdiagnosed as Vitiligo cases. In order to completely eliminate Kala-azar in Southeast Asia, proper identification of various routes of the disease is essential, which could efficiently distinguish between cured PKDL and active PKDL as well as active PKDL from other cross disease like Leprosy and Vitiligo. Till now very less work has been done towards biomarker identification for PKDL from patients’ plasma. Most of the methods for disease identification are based on highly invasive tissue biopsy followed by PCR/qPCR. Recently investigations from our group have demonstrated the presence of novel glycoproteins in the circulating immune complexes (CICs) from serum, as biomarkers for early identification of PKDL patients. An Immune complex (IC), sometimes called an antigen-antibody complex, is a molecule formed from the integral binding of an antibody to a soluble antigen. After an antigen-antibody reaction, the immune complexes can be subject to any number of responses, including complement deposition, opsonisation, phagocytosis, or processing by proteases. Accumulation of ICs leads to a broad spectrum of pro-inflammatory effects, including activation of the complement cascade and induction of cytokine secretion. These complexes may also be deposited in tissues and vessel walls, leading to inflammation, tissue damage and, ultimately, disease manifestations. Immune complexes also affect disease progression and outcome in various disorders through the induction of pro-inflammatory or anti-inflammatory cytokines. In the present study we hypothesize that the CICs’ proteome is altered among PKDL patients with different dermal manifestations (Macular and Polymorphic) as compared to Cured individuals (CR) and Healthy controls (HI). The aim of this current study is to identify differentially expressed CIC proteomic profile among different forms PKDL patients as compared to HI. The differential protein expression of specific unique peptide fragments, representing specific proteins, could be used as diagnostic biomarkers in early detection of both Macular and Polymorphic PKDL cases. In this prospective study, we included PKDL patients with Macular and/or Polymorphic lesion, Cured individuals and HI. Among the enrolled patients, blood samples were collected from 20 primarily confirmed PKDL patients with Macular lesions, 20 primarily confirmed PKDL patients with Polymorphic lesions, 12 Cured individuals previously suffering from PKDL and 12 Healthy individuals; collected during the period of 2015-2016, stored at -80°C. Next the CICs were purified from PKDL patients’ plasma and LC MS/MS analysis was performed using Q-ExactivePlusOrbitrap mass spectrometer. This work for the first time revealed the differential CICs proteome profile among different forms of PKDL patients as compared to their Cured and Healthy counterparts.

Dataset Information

Iron trafficking in patients with Indian Post kala-azar dermal leishmaniasis.

Publications

Iron trafficking in patients with Indian Post kala-azar dermal leishmaniasis.

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