Iron chelators modulate the fusogenic properties of Salmonella-containing phagosomes.

In macrophages, the divalent cations transporter Nrampl is recruited from the lysosomal compartment to the membrane of phagosomes formed in these cells. Nramp1 mutations cause susceptibility to infection with intracellular pathogens such as Salmonella and Mycobacterium. Intracellular survival of Salmonella involves segregation in an endomembrane compartment (Salmonella-containing vacuole, SCV) that remains negative for the mannose-6-phosphate receptor (M6PR) and that is inaccessible to the endocytic pathway. Expression of Nrampl at the membrane of SCVs stimulates both acquisition of M6PR and accessibility to newly formed endosomes. The possible role of Nrampl-mediated iron transport on SCV maturation was investigated with membrane-permeant iron chelators. Pretreatment of primary macrophages from Nramp1 mutant mice or of RAW264.7 macrophages (from BALB/c mice bearing an Nramp1[sup D169]-deficient allele) with either desferrioxamine or salicylaldehyde isocotinoyl hydrazone restored recruitment of M6PR and delivery of the fluid phase marker rhodamine dextran to SCVs to levels similar to those seen in macrophages expressing WT Nramp1. The effect was specific and dose-dependent and could be abrogated by preincubation with excess iron. These data suggest that Nrampl-mediated deprivation of iron and possibly of other divalent metals in macrophages antagonizes the ability of Salmonella to alter phagosome maturation. [ABSTRACT FROM AUTHOR]