科研之友
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摘要
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. Author Summary Infection with the protozoan parasite Leishmania causes significant human disease in many parts of the world, particularly in the Middle East, India and South America. The parasite is transmitted by sand flies, which are difficult to control and are becoming increasingly common in urban areas. 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 therefore 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. Acquiring iron is particularly challenging inside macrophages, which play an important role in host iron homeostasis and export iron extracellularly through the membrane transporter ferroportin. We found that Leishmania amazonesis induces their host macrophages to produce hepcidin, a peptide that triggers internalization and degradation of ferroportin. This strategy increases the macrophage intracellular iron pool, and stimulates Leishmania replication. These results suggest that defects in iron homeostasis, which occur frequently in the human population, can have an important role in susceptibility to Leishmania infections.
- 出版日期2014-1
