Leishmania-Mediated Inhibition of Iron Export Promotes Parasite Replication in Macrophages

 Rym Ben-Othman¹, Andrew R. Flannery¹, Danilo C. Miguel¹, Diane M. Ward², Jerry Kaplan²,Norma W. Andrews¹*

PLOS Pathogens. January 2014 | Volume 10 | Issue 1 | e1003901

Speaker: Chung-Ching Kuo (郭重慶)                          Time: 15:00~16:00, Dec. 30, 2015

Commentator: Jyh-Wei Shin, Ph.D. (辛致煒 教授)    Place: Room 601

Abstract:

Leishmania is a genus of trypanosomes that are responsible for the disease Leishmaniasis, which is found in parts of the tropics, subtropics, and southern Europe. About 2 million new cases occur each year. They are spread by sandflies and their primary hosts are vertebrates. Leishmaniaparasites infect macrophages, which are important for organismal iron homeostasis. Iron is essential for the intracellular replication of Leishmania, but the mechanism how parasites compete with the iron export function of their host cell is not clear [1]. In this study, authors show that infection with L. amazonensis inhibits ferroportin expression in macrophages. Ferroportin, a membrane protein specialized in iron export which is expressed in macrophage and used to release iron stored intracellularly into the circulation. When macrophage infected by Leishmania amazonensis, Hepcidin, a peptide hormone, could be upregulated to trigger the ferroportin degradation. Hepcidin-deficient and wild-type overexpressing mutant ferroportin macrophages will inhibit Parasite replication. On the contrary, adding exogenous hepcidin or expressing of dominant negative ferroportin would enhance parasite growth. [2] Most importantly, authors try a way to restore the infectivity of mutant parasite strains defective in iron acquisition by using dominant-negative ferroportin and macrophages from flatiron mice, a mouse model for human type IV hereditary hemochromatosis. Thus, inhibition of ferroportin expression is a specific strategy that L. amazonensis use to inhibit iron export and promote their own intracellular growth.

References:

1.  Bidyottam Mittra, Mauro Cortez, Andrew Haydock, Gowthaman Ramasamy, Peter J. Myler and Norma W. Andrews. Iron uptake controls the generation of Leishmania infective forms through regulation of ROS levels. J. Exp. Med. 2013 Vol. 210 No. 2.