Trypanosomatid protozoan parasites lack a functional heme biosynthetic pathway, so must acquire heme from the environment to survive. However, the molecular pathway responsible for heme acquisition by these organisms is unknown. Here we show that
L. amazonensis
LHR1, a homolog of the
C. elegans
plasma membrane heme transporter HRG-4, functions in heme transport. Tagged LHR1 localized to the plasma membrane and to endocytic compartments, in both
L. amazonensis
and mammalian cells. Heme deprivation in
L. amazonensis
increased
LHR1
transcript levels, promoted uptake of the fluorescent heme analog ZnMP, and increased the total intracellular heme content of promastigotes. Conversely, deletion of one
LHR1
allele reduced ZnMP uptake and the intracellular heme pool by approximately 50%, indicating that LHR1 is a major heme importer in
L. amazonensis
. Viable parasites with correct replacement of both
LHR1
alleles could not be obtained despite extensive attempts, suggesting that this gene is essential for the survival of promastigotes. Notably, LHR1 expression allowed
Saccharomyces cerevisiae
to import heme from the environment, and rescued growth of a strain deficient in heme biosynthesis. Syntenic genes with high sequence identity to
LHR1
are present in the genomes of several species of
Leishmania
and also
Trypanosoma cruzi
and
Trypanosoma brucei
, indicating that therapeutic agents targeting this transporter could be effective against a broad group of trypanosomatid parasites that cause serious human disease.
Tamoxifen effectively kills several Leishmania species and its activity against the parasite is increased by a modulation of the host cell intravacuolar pH induced by the drug.
Tritryps diseases are devastating parasitic neglected infections caused by Leishmania spp., Trypanosoma cruzi and Trypanosoma brucei subspecies. Together, these parasites affect more than 30 million people worldwide and cause high mortality and morbidity. Leishmaniasis comprises a complex group of diseases with clinical manifestation ranging from cutaneous lesions to systemic visceral damage. Antimonials, the first-choice drugs used to treat leishmaniasis, lead to high toxicity and carry significant contraindications limiting its use. Drug-resistant parasite strains are also a matter for increasing concern, especially in areas with very limited resources. The current scenario calls for novel and/or improvement of existing therapeutics as key research priorities in the field. Although several studies have shown advances in drug discovery towards leishmaniasis in recent years, key knowledge gaps in drug discovery pipelines still need to be addressed. In this review we discuss not only scientific and non-scientific bottlenecks in drug development, but also the central role of public-private partnerships for a successful campaign for novel treatment options against this devastating disease.
Leishmania parasites infect macrophages, cells that play an important role in organismal iron homeostasis. By expressing ferroportin, a membrane protein specialized in iron export, macrophages release iron stored intracellularly into the circulation. Iron is essential for the intracellular replication of Leishmania, but how the parasites compete with the iron export function of their host cell is unknown. Here, we show that infection with Leishmania amazonensis inhibits ferroportin expression in macrophages. In a TLR4-dependent manner, infected macrophages upregulated transcription of hepcidin, a peptide hormone that triggers ferroportin degradation. Parasite replication was inhibited in hepcidin-deficient macrophages and in wild type macrophages overexpressing mutant ferroportin that is resistant to hepcidin-induced degradation. Conversely, intracellular growth was enhanced by exogenously added hepcidin, or by expression of dominant-negative ferroportin. Importantly, dominant-negative ferroportin and macrophages from flatiron mice, a mouse model for human type IV hereditary hemochromatosis, restored the infectivity of mutant parasite strains defective in iron acquisition. Thus, inhibition of ferroportin expression is a specific strategy used by L. amazonensis to inhibit iron export and promote their own intracellular growth.
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