Sequestration and scavenging of iron in infection

Abstract

The proliferative capability of many invasive pathogens is limited by the bioavailability of iron. Pathogens have thus developed strategies to obtain iron from their host organisms. In turn, host defense strategies have evolved to sequester iron from invasive pathogens. This review explores the mechanisms employed by bacterial pathogens to gain access to host iron sources, the role of iron in bacterial virulence, and iron-related genes required for the establishment or maintenance of infection. Host defenses to limit iron availability for bacterial growth during the acute-phase response and the consequences of iron overload conditions on susceptibility to bacterial infection are also examined. The evidence summarized herein demonstrates the importance of iron bioavailability in influencing the risk of infection and the ability of the host to clear the pathogen.

Fig 1

Schematic of bacterial heme acquisition systems. (A) In Gram-negative bacteria, heme binds an outer membrane (OM) receptor that transports it to the periplasmic space by using energy transduced from the cytosolic membrane via the TonB/ExbBD complex. A periplasmic binding protein (PBP) transfers the heme to a membrane-spanning permease, and transport across the cell membrane is mediated by an ATPase. (B) In Gram-positive bacteria, the absence of an OM eliminates the need for TonB/ExbBD and the PBP. In general, a cell wall-anchored surface receptor binds heme and relays it to an intermediate cell wall-anchored receptor (labeled a transfer protein in this diagram), which then transfers the heme to the binding protein and permease of an ABC transporter at the cell membrane. Energy for transport across the membrane is provided by an ATPase. Peptidoglycan is shown for orientation.

Fig 2

Iron-related APPs coordinate hypoferremia in response to infection and inflammation. Infection and inflammation result in the production of proinflammatory cytokines, such as IL-6, by immune effector cells. In turn, proinflammatory cytokines bind to cognate receptors on hepatocytes, triggering a signaling cascade that results in increased synthesis (indicated by green arrows) of several iron-related APPs. Decreased release of iron into the circulation is facilitated by hepcidin upregulation, which results in a net decrease in plasma iron by binding to and promoting degradation of ferroportin on hepatocytes, RE macrophages, and duodenal enterocytes. Increased intracellular iron storage results from the induction of ferritin. Decreased bioavailability of nonheme iron is mediated by ceruloplasmin's ferroxidase activity, combined with binding of Fe³⁺ by lactoferrin. Decreased availability of extracellular heme iron is mediated by the induction of hemopexin, which results in the binding of free heme, while haptoglobin binds free hemoglobin and promotes its clearance. This coordinated response is thought to deprive invading microorganisms of iron while simultaneously protecting tissue from unnecessary oxidative stress resulting from the interaction of iron with immune mediators.