Intracellular iron availability modulates the requirement for Leishmania Iron Regulator 1 (LIR1) during macrophage infections |
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| Institution: | 1. Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA;2. Department of Animal and Avian Sciences, University of Maryland, College Park, MD, USA;3. Department of Physiology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil;1. UMR 5175 CEFE, CNRS–Université de Montpellier–Université P. Valéry–EPHE, 1919 Route de Mende, 34293 Montpellier, Cedex 5, France;2. UMR 5290 MIVEGEC, CNRS–IRD–Université de Montpellier, 911 Avenue Agropolis BP 64501, 34394 Montpellier, Cedex 5, France;1. Dipartimento di Medicina Veterinaria, Università di Bari, 70010, Valenzano, Bari, Italy;2. Dipartimento di Scienze Veterinarie, Università di Messina, 98168, Messina, Italy;1. Mitrani Department of Desert Ecology, Swiss Institute for Dryland Environmental and Energy Research, Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, 8499000 Midreshet Ben-Gurion, Israel;2. Wyler Department of Dryland Agriculture, French Associates Institute for Agriculture and Biotechnology of Drylands, Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, 8499000 Midreshet Ben-Gurion, Israel |
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| Abstract: | The Leishmania plasma membrane transporter Leishmania Iron Regulator 1 (LIR1) facilitates iron export and is required for parasite virulence. By modulating macrophage iron content, we investigated the host site where LIR1 regulates Leishmania amazonensis infectivity. In bone marrow-derived macrophages, LIR1 null mutants demonstrated a paradoxical increase in virulence during infections in heme-depleted media, while wild-type growth was inhibited under the same conditions. Loading the endocytic pathway of macrophages with cationized ferritin prior to infection reversed the effect of heme depletion on both strains. Thus, LIR1 contributes to Leishmania virulence by protecting the parasites from toxicity resulting from iron accumulation inside parasitophorous vacuoles. |
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| Keywords: | Heme Cationic ferritin Amastigotes Endocytic pathway Virulence Drug target |
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