Abstract
Genetic and dietary forms of iron overload have distinctive clinical and pathophysiological features. HFE-associated hereditary hemochromatosis is characterized by overwhelming intestinal iron absorption, parenchymal iron deposition, and macrophage iron depletion. In contrast, excessive dietary iron intake results in iron deposition in macrophages. However, the functional consequences of genetic and dietary iron overload for the control of microbes are incompletely understood. Using Hfe+/+ and Hfe−/− mice in combination with oral iron overload in a model of Salmonella enterica serovar Typhimurium infection, we found animals of either genotype to induce hepcidin antimicrobial peptide expression and hypoferremia following systemic infection in an Hfe-independent manner. As predicted, Hfe−/− mice, a model of hereditary hemochromatosis, displayed reduced spleen iron content, which translated into improved control of Salmonella replication. Salmonella adapted to the iron-poor microenvironment in the spleens of Hfe−/− mice by inducing the expression of its siderophore iron-uptake machinery. Dietary iron loading resulted in higher bacterial numbers in both WT and Hfe−/− mice, although Hfe deficiency still resulted in better pathogen control and improved survival. This suggests that Hfe deficiency may exert protective effects in addition to the control of iron availability for intracellular bacteria. Our data show that a dynamic adaptation of iron metabolism in both immune cells and microbes shapes the host-pathogen interaction in the setting of systemic Salmonella infection. Moreover, Hfe-associated iron overload and dietary iron excess result in different outcomes in infection, indicating that tissue and cellular iron distribution determines the susceptibility to infection with specific pathogens.
Highlights
HFE encodes an atypical MHC class I molecule which plays a major role in the regulation of iron homeostasis under basal conditions (Feder et al, 1996; Ludwiczek et al, 2004)
To better understand the influence of Hfe and dietary iron loading on iron homeostasis and the outcome of infection, we used a well-established model of systemic Salmonella infection
Congenic WT and Hfe−/− mice were systemically infected with 500 colony-forming units (CFU) of Salmonella enterica serovar Typhimurium ATCC14028
Summary
HFE encodes an atypical MHC class I molecule which plays a major role in the regulation of iron homeostasis under basal conditions (Feder et al, 1996; Ludwiczek et al, 2004). HFE binds to transferrin receptor 1 (TfR1) lowering its affinity for iron-laden transferrin (Feder et al, 1998; Lebrón et al, 1998; Bennett et al, 2000) This interaction controls cellular iron acquisition while modifying the expression of the key iron-regulatory hormone Hamp (Ahmad et al, 2002; Nicolas et al, 2003; Ludwiczek et al, 2005; Vujic Spasic et al, 2008). The latter mechanism involves the sensing of circulating iron levels by TfR1 and TfR2, which reciprocally complex with HFE expressed on hepatocytes (Schmidt et al, 2008; Wallace et al, 2009). Macrophages lacking HFE display an iron-poor phenotype which has been attributed to enhanced iron export (Cairo et al, 1997; Drakesmith et al, 2002; Wang et al, 2003)
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