Hepcidin mediated iron homoeostasis as immune regulator in visceral leishmaniasis patients

Abstract

Aim: Iron is key ingredient for immunosurveillance and host-pathogen interaction. Intracellular pathogen steals the iron from the host, but how parasite orchestrates iron acquisition and affects immune responses remains controversial. We aimed to study the iron homeostasis in visceral leishmaniasis (VL) and its influence on immune machinery. Methods and Results: This study was performed on purified monocytes and T-cells, peripheral blood mononuclear cells and splenic aspirates for transcriptional analyses of iron homeostasis (hepcidin, DMT-1, transferrin receptor, ferroportin) and immune modulations (IFN-ϒ, HLA-DR, IL-10, iNOS, IL-6). Serum/plasma were used for determination of iron, total/transferrin iron binding capacity and anti-leishmania antibody titres in cases. We report that VL induced perturbation in iron homeostasis may cause immune dysfunctions. VL cases had decreased iron uptake by transferrin dependent and independent routes while elevated hepcidin, degraded sole iron exporter ferroportin. Therefore, it appears that perturbation in iron homeostasis has essential role in HLA-DR mediated antigen presentation and innate armory by downregulating iNOS as well as altering IFN-ϒ, IL-6, IL-10 profiles. Conclusion: The iron homeostasis by hepcidin can serves as one of the crucial determinants for regulating immune cell signaling therefore, targeting iron metabolism, specifically hepcidin alone or in combination with agonists can serve to clear infection.

Micronutrient levels and their effect on the prognosis of visceral leishmaniasis treatment; a prospective cohort study.

“…Higher patient iron level increases the treatment success rate of visceral leishmaniasis. This nding supports the results of previously published work [77]. This is due to the crucial role of iron in red blood cell production that is used to transport essential substances, including the antileishmaniasis drugs [78].…”

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

“…Intracellular organisms like Francisella tularensis upregulate DMT-1 expression [37] and similarly, at lesional sites of PKDL cases, the increased mRNA expression of DMT-1 endorsed its possible utilization by parasites to enhance influx of iron (Fig 1E). However, in VL, an unaltered expression of DMT-1 was observed, and could be attributed to it being an acute disease vis-a-vis the chronicity of PKDL [31].…”

“…Leishmania upon scavenging iron from LIP causes activation of iron-sensing proteins, and the resultant enhanced interaction of Iron Responsive Elements (IREs) with TfR1 translates into an increased uptake of iron [29]. Additionally, as patients with PKDL demonstrate a mixed Th1-Th2 cytokine milieu with a tilt towards Th2, the increased levels of IL4 and IL-10 [30] too can facilitate an increased mRNA expression of TfR1 [31]. However, this did not occur in patients with VL, as a decreased expression of TfR1 was reported [31].…”

“…Additionally, as patients with PKDL demonstrate a mixed Th1-Th2 cytokine milieu with a tilt towards Th2, the increased levels of IL4 and IL-10 [30] too can facilitate an increased mRNA expression of TfR1 [31]. However, this did not occur in patients with VL, as a decreased expression of TfR1 was reported [31]. Similarly, studies regarding Legionella also reported decreased levels of TfR1 in activated macrophages which were attributed to the IFN-γ mediated pro-inflammatory environment [32].…”

“…Ferroportin (Fpn) is an established mammalian iron exporter whose regulation is critical for iron homeostasis, and its alterations can translate into iron deficiency or iron overload. It has been proposed that to increase the availability of iron, host cell derived hepcidin promotes the degradation of Fpn which translates into increased availability of iron during infections with L. amazonensis [56,57], and has been substantiated in patients with VL [31]. However, in L. donovani models of infection where despite the levels of Hepcidin being raised, the mRNA expression of Fpn too was elevated [57].…”