Heme Uptake Mediated by LHR1 Is Essential for Leishmania amazonensis Virulence
| Autor: | Andrew R. Flannery, Danilo C. Miguel, Norma W. Andrews, Bidyottam Mittra |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Phagocytosis
Immunology Protozoan Proteins Virulence Heme Biology Microbiology Mice chemistry.chemical_compound Animals Amastigote Leishmania Infectivity chemistry.chemical_classification Macrophages biology.organism_classification Infectious Diseases Enzyme chemistry Parasitology Fungal and Parasitic Infections Gene Deletion Intracellular |
| Zdroj: | Infection and Immunity. 81:3620-3626 |
| ISSN: | 1098-5522 0019-9567 |
| Popis: | The protozoan parasite Leishmania amazonensis is a heme auxotroph and must acquire this essential factor from the environment. Previous studies showed that L. amazonensis incorporates heme through the transmembrane protein LHR1 (L eishmania H eme R esponse 1). LHR1 -null promastigotes were not viable, suggesting that the transporter is essential for survival. Here, we compared the growth, differentiation, and infectivity for macrophages and mice of wild-type, LHR1 -single-knockout ( LHR1/ Δ lhr1 ), and LHR1 -complemented ( LHR1/ Δ lhr1 plus LHR1 ) L. amazonensis strains. LHR1/ Δ lhr1 promastigotes replicated poorly in heme-deficient media and had lower intracellular heme content than wild-type parasites. LHR1/ Δ lhr1 promastigotes were also less effective in reducing ferric iron to ferrous iron, a reaction mediated by the heme-containing parasite enzyme LFR1 ( Leishmania Ferric Reductase 1). LHR1/ Δ lhr1 parasites differentiated normally into aflagellated forms expressing amastigote-specific markers but were not able to replicate intracellularly after infecting macrophages. Importantly, the intracellular growth of LHR1/ Δ lhr1 amastigotes was fully restored when macrophages were allowed to phagocytose red blood cells prior to infection. LHR1/ Δ lhr1 parasites were also severely defective in the development of cutaneous lesions in mice. All phenotypes observed in LHR1/ Δ lhr1 L. amazonensis were rescued by expression of episomal LHR1 . Our results reveal the importance of efficient heme uptake for L. amazonensis replication and vertebrate host infectivity, reinforcing the potential usefulness of LHR1 as a target for new antileishmanial drugs. |
| Databáze: | OpenAIRE |
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