Iron in intracellular infection: to provide or to deprive?

Abstract

Due to their chemical versatility, transition metals were incorporated as cofactors for several basic metabolic pathways in living organisms. This same characteristic makes them potentially harmful, since they can be engaged in deleterious reactions like Fenton chemistry. As such, organisms have evolved highly specialized mechanisms to supply their own metal needs while keeping their toxic potential in check. This dual character comes into play in host-pathogen interactions, given that the host can either deprive the pathogen of these key nutrients or exploit them to induce toxicity toward the invading agent. Iron stands as the prototypic example of how a metal can be used to limit the growth of pathogens by nutrient deprivation, a mechanism widely studied in Mycobacterium infections. However, the host can also take advantage of iron-induced toxicity to control pathogen proliferation, as observed in infections caused by Leishmania. Whether we may harness either of the two pathways for therapeutical purposes is still ill-defined. In this review, we discuss how modulation of the host iron availability impacts the course of infections, focusing on those caused by two relevant intracellular pathogens, Mycobacterium and Leishmania.

Keywords: Leishmania; Mycobacterium; immunity; infection; transition metal.

Figure 1

Transition metals in immunity against intracellular pathogens. Upon entry into the host cell, the pathogen is able to retrieve metals from its surroundings to incorporate them in mettaloproteins strictly required for its survival. The pathogen uses dedicated transporters and specialized proteins [e.g., siderophores (Hider and Kong, 2010), high-affinity iron chelating compounds] to acquire metals from the cytoplasmic pools or by hijacking the cell pathways of metal acquisition (for example, Mycobacterium and Leishmania have access to transferrin-bound iron in the endocytic pathway). One of the countermeasures employed by the host cell to reduce the proliferation of the pathogen is metal deprivation (A). This is achieved by pumping out the metal from the phagosome, mediated by metal transporters such as SLC11A1, which is recruited to the phagosomal membrane, where it transports iron and manganese out of this compartment. The metal can then be diverted into storage [e.g., the iron-storage ferritin is induced during infection with Salmonella (Nairz et al., 2007) and Mycobacterium (Silva-Gomes et al., 2013b)] or exported [e.g., ferroportin, an iron exporter that localizes to the cellular membrane, is induced in macrophages infected with Mycobacterium (Van Zandt et al., 2008) and Salmonella (Nairz et al., 2007)]. On the other hand, the host cell can explore the toxicity of transition metal and direct them to the microbial invader (B). During infection, metal transporters such as copper transport 1 (CTR1) (White et al., 2009) are induced, and transport the metal from the extracellular environment. Metals are also mobilized from intracellular storage [e.g., macrophages mobilize zinc from intracellular stores when infected with M. tuberculosis or E. coli (Botella et al., 2011)], which will then accumulate in the phagosome by the action of metal transporters, such as the copper transporter ATP7A (White et al., 2009).