Nramp1 and Other Transporters Involved in Metal Withholding during Infection

Abstract

During the course of infection, many natural defenses are set up along the boundaries of the host-pathogen interface. Key among these is the host response to withhold metals to restrict the growth of invading microbes. This simple act of nutritional warfare, starving the invader of an essential element, is an effective means of limiting infection. The physiology of metal withholding is often referred to as "nutritional immunity," and the mechanisms of metal transport that contribute to this host response are the focus of this review.The rationale for host metal withholding against invading pathogens seems intuitive; restriction of any nutrient required for pathogen survival should combat infection. But why metals? The answer to this question becomes crystal clear when one recognizes that iron is required for nearly all life forms, including pathogenic bacteria, with a few rare exceptions that rely on manganese instead (1-7). Iron is essential for ATP production and other metabolic pathways, but its concentration is limited to avoid production of ROS 2 catalyzed by excess levels of this redox-active metal (8). In some organisms, manganese can substitute for redox-active iron to protect against oxidative stress (9, 10). Moreover, most pathogens require manganese to produce their own superoxide dismutase activity to thwart oxidative killing mechanisms exerted by the host (11-13). Iron and manganese have similar ionic radii, have a divalent charge state under physiological conditions, have similar coordination chemistries, and have cellular concentrations in the micromolar range. Consequently, it comes as no surprise that these two metals also share membrane transporters, despite their different cellular functions and distributions. Restriction of iron and/or manganese provides a broad-spectrum metabolic "antidote" against all pathogenic infections, and the common transport pathways used by these metals present selective targets to limit their availability. Although many other immune responses contribute to the fight against infection, metal withholding represents a major force in host defense with combat controlled through transport.The concept of nutritional immunity through metal withholding is largely based on the observations that the iron content of the human diet profoundly affects infectious diseases such as malaria, brucellosis, and tuberculosis (14, 15). Iron overload states such as sickle cell anemia and ␤-thalassemia increase the risk of infection (16 -18). Hereditary hemochromatosis, an inherited disorder of iron metabolism, is also linked to susceptibility to some pathogens (17, 19 -22). Iron deficiency, on the other hand, is associated with decreased survival of individuals infected with HIV and other agents (23). Still, high iron is positively associated with viral load and mortality in HIV (24 -26), suggesting that an optimal balance of iron is necessary. In general terms, low iron status is protective, whereas elevated iron levels promote infection (27, 28). The complexity of host-pathogen interact...

Iron and infection

“…The weight of the evidence now indicates that Nramp1 transports iron and manganese out of the phagocytic vacuole into the cytoplasm [46], thereby depleting the phagosome of these essential metals. This view is supported by most of the direct experimental evidence, by the involvement of Nramp1 in iron recycling from senescent erythrocytes [47], by the similarity of Nramp1 to DMT1 whose transport properties are well characterized, and by the evidence that the function of Nramp1 may be carried out in teleost fish by a duplicated paralog of DMT1 [48].…”

NRAMP1 Polymorphisms like Susceptibility Marker in Mexican Focus of Cutaneous Leishmaniasis

“…This mutated allele also causes an appropriate level of Fe +2 that allows development of microorganisms because it has been suggested that affected NRAMP1 reduces iron release from macrophages. Then iron accumulates in the liver and spleen when erythrophagocytosis happens and when there are changes in level of iron and other metals, ROS- (Reactive Oxygen Species-) regulated signaling is altered, in the same way as inflammatory pathway activation, a very important antimicrobial mechanism [38]. …”

Transition Metals and Virulence in Bacteria

“…In response to infection, neutrophils and macrophages express the natural resistance–associated macrophage protein 1 (Nramp1), which depletes the phagosome of manganese and, to a lesser extent, iron (67, 142). Bacterial manganese acquisition systems are important for resisting Nramp1-mediated manganese restriction and may contribute differentially, such as in S. enterica infection of stimulated macrophages.…”