Abstract
BackgroundThe control over iron homeostasis is critical in host-pathogen-interaction. Iron plays not only multiple roles for bacterial growth and pathogenicity, but also for modulation of innate immune responses. Hepcidin is a key regulator of host iron metabolism triggering degradation of the iron exporter ferroportin. Although iron overload in humans is known to increase susceptibility to Burkholderia pseudomallei, it is unclear how the pathogen competes with the host for the metal during infection. This study aimed to investigate whether B. pseudomallei, the causative agent of melioidosis, modulates iron balance and how regulation of host cell iron content affects intracellular bacterial proliferation.Principal findingsUpon infection of primary macrophages with B. pseudomallei, expression of ferroportin was downregulated resulting in higher iron availability within macrophages. Exogenous modification of iron export function by hepcidin or iron supplementation by ferric ammonium citrate led to increased intracellular iron pool stimulating B. pseudomallei growth, whereas the iron chelator deferoxamine reduced bacterial survival. Iron-loaded macrophages exhibited a lower expression of NADPH oxidase, iNOS, lipocalin 2, cytokines and activation of caspase-1. Infection of mice with the pathogen caused a diminished hepatic ferroportin expression, higher iron retention in the liver and lower iron levels in the serum (hypoferremia). In vivo administration of ferric ammonium citrate tended to promote the bacterial growth and inflammatory response, whereas limitation of iron availability significantly ameliorated bacterial clearance, attenuated serum cytokine levels and improved survival of infected mice.ConclusionsOur data indicate that modulation of the cellular iron balance is likely to be a strategy of B. pseudomallei to improve iron acquisition and to restrict antibacterial immune effector mechanisms and thereby to promote its intracellular growth. Moreover, we provide evidence that changes in host iron homeostasis can influence susceptibility to melioidosis, and suggest that iron chelating drugs might be an additional therapeutic option.
Highlights
Iron plays a central role at the host-pathogen interface, because it is a pivotal nutrient for microbial pathogens and their mammalian hosts
This study aimed to investigate whether B. pseudomallei, the causative agent of melioidosis, modulates iron balance and how regulation of host cell iron content affects intracellular bacterial proliferation
Our data indicate that modulation of the cellular iron balance is likely to be a strategy of B. pseudomallei to improve iron acquisition and to restrict antibacterial immune effector mechanisms and thereby to promote its intracellular growth
Summary
Iron plays a central role at the host-pathogen interface, because it is a pivotal nutrient for microbial pathogens and their mammalian hosts. Both require the metal as a cofactor or as prosthetic group for key enzymes involved in fundamental cellular functions and metabolic processes [1]. Macrophages are essential for immune function and contribute to maintenance of iron homeostasis. They acquire heme iron by phagocytosis of senescent or damaged erythrocytes and receptor-mediated uptake of proteins binding extracellular free heme (via interaction of hemopexin with CD91) or haemoglobin (via interaction of haptoglobin with CD163). This study aimed to investigate whether B. pseudomallei, the causative agent of melioidosis, modulates iron balance and how regulation of host cell iron content affects intracellular bacterial proliferation
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