Abstract
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.
Highlights
Intracellular parasites must obtain essential nutrients from their host cells
With domestic dogs serving as reservoirs of the disease and global travel increasing the population of infected human patients, the overall burden of leishmaniasis is on the rise. In mammals these parasites replicate inside macrophages, and need strategies to survive within a cell that is specialized in killing pathogens
Earlier work demonstrated that iron is one of the essential nutrients that Leishmania must acquire from host cells to survive
Summary
Intracellular parasites must obtain essential nutrients from their host cells. Iron is a vital nutritional resource for mammalian hosts and for many pathogens, acting as an essential cofactor of proteins and enzymes involved in metabolic pathways. Iron is normally found in the insoluble, oxidized Fe3+ form associated with carrier proteins such as transferrin and ferritin. After endocytosis mediated by transferrin receptors, Fe3+ is reduced to the soluble Fe2+ form and translocated to the cytosol. Iron may be utilized by the host, stored as complex with ferritin, or exported out of the cells. The pool of available iron within mammalian cells is determined by a carefully orchestrated balance between uptake through plasma membrane and endosomal receptors/transporters and cellular export
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