Leishmania-mediated inhibition of iron export promotes parasite replication in macrophages.
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.
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
Rym
R
Ben-Othman
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
Andrew R
AR
Flannery
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
Danilo C
DC
Miguel
Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
Diane M
DM
Ward
Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
Jerry
J
Kaplan
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
Norma W
NW
Andrews
D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D064451:Hepcidins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007891:Leishmania / Q000378:metabolism*; D007896:Leishmaniasis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000098742:Ferroportin
D027682:Cation Transport Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D000098742:Ferroportin; D007501:Iron