Pathways of iron acquisition and utilization in Leishmania

Flannery, Andrew R.; Renberg, Rebecca L.; Andrews, Norma W.

doi:10.1016/j.mib.2013.07.018

Cited by 44 publications

(33 citation statements)

References 43 publications

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“…3E). This data reconfirmed the role of iron as a vital nutrient for Leishmania parasites residing in the phagolysosomal niche (34).…”

Section: Resultssupporting

confidence: 71%

“…Growth and survival of Leishmania , like other intracellular pathogens, is critically dependent on the availability of iron and their ability to scavenge it from the surroundings (34, 46, 47). Since iron pool in mammals is tightly regulated, the battle between the host and the pathogen for this essential micronutrient has often been found to be a key determinant of the infection outcome (48).…”

Section: Discussionmentioning

confidence: 99%

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Leishmaniainfection triggers hepcidin-mediated proteasomal degradation of Nramp1 resulting in increased phagolysosomal iron availability

Banerjee

Datta

2019

Preprint

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word count: 250 20 Text word count: 5459 21 2 Abstract 22 Natural resistance associated macrophage protein 1 (Nramp1) was discovered as a genetic 23 determinant of resistance against multiple intracellular pathogens, including Leishmania. It 24 encodes a transmembrane protein of the phago-endosomal vesicles, where it functions as an iron 25 transporter. But how Nramp1 expression is regulated in an infected macrophage is unknown. Its 26 role in controlling iron availability to the intracellular pathogens and in determining the final 27 outcome of an infection also remains to be fully deciphered. Here we report that Nramp1 protein 28 abundance undergoes temporal changes in Leishmania major infected macrophages. At 12 hours 29 post infection, there was drastic lowering of Nramp1 level accompanied by increased 30 phagolysosomal iron availability and enhanced parasite growth. Leishmania infection-induced 31 downregulation of Nramp1 was found to be caused by ubiquitin-proteasome degradation 32 pathway. In fact, blocking of Nramp1 degradation with proteasome inhibitor resulted in 33 depletion of phagolysosomal iron pool with significant reduction in the number of intracellular 34 parasites. Further, we uncovered that this degradation process is mediated by the iron regulatory 35 peptide hormone hepcidin that binds to Nramp1. Interestingly, Nramp1 protein level was 36 restored to normalcy after 30 hours of infection with a concomitant drop in the phagolysosomal 37 iron level, which is suggestive of a host counter defense strategy to deprive the pathogen of this 38 essential micronutrient. Taken together, our study implicates Nramp1 as a central player in the 39 host-pathogen battle for iron. It also unravels Nramp1 as a novel partner for hepcidin. The 40 hitherto unidentified 'hepcidin-Nramp1 axis' may have a broader role in regulating macrophage 41 iron homeostasis.42 43 3 Importance 44 Leishmania parasites are the causative agents of a group of neglected tropical diseases called 45 leishmaniasis. They reside within the phagolysosomes of mammalian macrophages. Since iron is 46 an essential micronutrient for survival and virulence, intracellular Leishmania must acquire it 47 from the tightly regulated macrophage iron pool. How this challenging task is accomplished 48 remains a fundamental question in Leishmania biology. We report here that Leishmania major 49 infection caused ubiquitin-proteasome-mediated degradation of natural resistance associated 50 macrophage protein 1 (Nramp1). Nramp1 being an iron exporter at the phago-endosomal 51 membrane, its degradation resulted in increased phagolysosomal iron availability thereby 52 stimulating parasite growth. We also uncovered that Nramp1 degradation is controlled by the 53 iron regulatory peptide hormone hepcidin. Interestingly, at a later stage of infection, Nramp1 54 protein level was restored to normalcy with simultaneous depletion of phagolysosomal iron. 55 Collectively, our study implicates Nramp1 as a central player in the host-pathogen struggle for 56 acquiring iron...

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“…3E). This data reconfirmed the role of iron as a vital nutrient for Leishmania parasites residing in the phagolysosomal niche (34).…”

Section: Resultssupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Leishmaniainfection triggers hepcidin-mediated proteasomal degradation of Nramp1 resulting in increased phagolysosomal iron availability

Banerjee

Datta

2019

Preprint

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“…216 Leishmania spp. amastigotes require iron from the host in order to survive and exert their pathogenicity 217 (Flannery et al, 2013) , and this could be related to the low MCHC in our sample. 218…”

Section: Introduction 48mentioning

confidence: 96%

Correlations between peripheral parasite load and common clinical and laboratory alterations in dogs with visceral leishmaniasis

Torrecilha

Utsunomiya

Bosco

et al. 2016

Preventive Veterinary Medicine

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(2016) Correlations between peripheral parasite load and common clinical and laboratory alterations in dogs with visceral leishmaniasis. Preventive Veterinary Medicine, 132 . pp. 83-87. Permanent WRAP URL:http://wrap.warwick.ac.uk/82952 Copyright and reuse:The Warwick Research Archive Portal (WRAP) makes this work by researchers of the University of Warwick available open access under the following conditions. Copyright © and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable the material made available in WRAP has been checked for eligibility before being made available.Copies of full items can be used for personal research or study, educational, or not-for-profit purposes without prior permission or charge. Provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. Intensity of peripheral parasite infection has an important role in the transmission of 25Leishmania spp. from one host to another. As parasite load quantification is still an expensive 26 procedure to be used routinely in epidemiological surveillance, the use of surrogate predictors may be 27 an important asset in the identification of dogs with high transmitting ability. The present study 28 examined whether common clinical and laboratory alterations can serve as predictors of peripheral 29 parasitism in dogs naturally infected with Leishmania spp. Thirty-seven dogs were examined in order 30 to establish correlations between parasite load (PL) in multiple peripheral tissues and common clinical 31 and laboratory findings in canine visceral leishmaniasis (CVL). Quantitative polymerase chain reaction 32 was employed to determine PL in conjunctival swabs, ear skin, peripheral blood and buffy coat. 33Additionally, a series of hematological, biochemical and oxidative stress markers were quantified. 34Correlations between net peripheral infection and severity of clinical alterations and variation in 35 laboratory parameters were assessed through a new analytical approach, namely Compressed Parasite 36Load Data (CPLD), which uses dimension reduction techniques from multivariate statistics to 37 summarize PL across tissues into a single variable. The analysis revealed that elevation in PL is 38 positively correlated with severity of clinical sings commonly observed in CVL, such as skin lesions, 39 ophthalmic alterations, onycogriphosis, popliteal lymphadenomegaly and low body mass. Furthermore, 40 increase in PL was found to be followed by intensification of non-regenerative anemia, neutrophilia, 41 eosinopenia, hepatic injury and oxidative imbalance. These results suggest that routinely used clinical 42 and laboratory exams can be predictive of intensity of peripheral parasite infection, which has an 43 important implication in the identification of dogs with high transmitting ability. 44 45

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“…In particular trypanosomatids, which include Trypanosoma cruzi , Trypanosoma brucei , and Leishmania sp . share a number of biological, biochemical, and molecular mechanisms, which includes: (i) the requirement of invertebrate and vertebrate hosts to complete their life‐cycle; (ii) the exposure to vertebrate blood during natural development in vectors and humans; (iii) their dependency of heme for normal cell growth (Chang and Chang ); (iv) the presence of specific mechanisms involved in hemoglobin/heme/iron trafficking (Lara et al, ; Patel et al, ; Huynh et al, ; Flannery et al, ). Importantly, since trypanosomatids lack a functional heme biosynthetic pathway, these parasites are absolutely dependent of an external source of heme for normal growth (Salzman et al, ; Lombardo et al, ).…”

Section: Does Reduced Respiratory Capacity and Increased Mitochondriamentioning

confidence: 99%

Modulation of mitochondrial metabolism as a biochemical trait in blood feeding organisms: the redox vampire hypothesis redux

Ferreira

Oliveira

Paes

et al. 2018

Cell Biology International

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Hematophagous organisms undergo remarkable metabolic changes during the blood digestion process, increasing fermentative glucose metabolism, and reducing respiratory rates, both consequence of functional mitochondrial remodeling. Here, we review the pathways involved in energy metabolism and mitochondrial functionality in a comparative framework across different hematophagous species, and consider how these processes regulate redox homeostasis during blood digestion. The trend across distinct species indicate that a switch in energy metabolism might represent an important defensive mechanism to avoid the potential harmful interaction of oxidants generated from aerobic energy metabolism with products derived from blood digestion. Indeed, in insect vectors, blood feeding transiently reduces respiratory rates and oxidant production, irrespective of tissue and insect model. On the other hand, a different scenario is observed in several unrelated parasite species when exposed to blood digestion products, as respiratory rates reduce and mitochondrial oxidant production increase. The emerging picture indicates that re-wiring of energy metabolism, through reduced mitochondrial function, culminates in improved tolerance to redox insults and seems to represent a key step for hematophagous organisms to cope with the overwhelming and potentially toxic blood meal.

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Pathways of iron acquisition and utilization in Leishmania

Cited by 44 publications

References 43 publications

Leishmaniainfection triggers hepcidin-mediated proteasomal degradation of Nramp1 resulting in increased phagolysosomal iron availability

Leishmaniainfection triggers hepcidin-mediated proteasomal degradation of Nramp1 resulting in increased phagolysosomal iron availability

Correlations between peripheral parasite load and common clinical and laboratory alterations in dogs with visceral leishmaniasis

Modulation of mitochondrial metabolism as a biochemical trait in blood feeding organisms: the redox vampire hypothesis redux

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