The iron link between malaria and invasive non-typhoid Salmonella infections

Abstract

Epidemiological studies have demonstrated an association between malaria and invasive non-typhoid Salmonella (NTS) infections, especially in children. We explore the role of iron as a possible cofactor in this association. Malarial disease, among others, is associated with enhanced erythrophagocytosis and inflammation, which increases the iron content of macrophages and thereby also the survival of Salmonella spp. within macrophages. Whether iron supplementation programs augment the risk of invasive NTS infections in malaria-endemic regions is an important global health issue that still needs to be determined.

Figure 1. Interaction of malaria and Salmonella with macrophage iron

Phagocytosis of both uninfected and infected RBCs (a) is increased during the blood stage malaria infection [83], which results in degradation of the RBCs by proteolytic enzymes into heme. (b) HO-1 converts heme into iron (and carbon monoxide and biliverdin). (c) Excess iron is transported to the cytosol via phagosomal transporters DMT-1 and Nramp-1 [24] and further processed: (i) stored in ferritin (d), and (ii) used in metabolic processes or released from the cell via ferroportin (e) [26, 79]. (f) Meanwhile, parasite products activate the innate immune system via Toll Like receptors (TLR) 2, 4 and 9 [84]. This systemic response during malaria induces hepatic hepcidin production; (e) hepcidin functions by blocking ferroportin [29, 78]. In addition, monocytes and macrophages also express hepcidin upon stimulation with various pro-inflammatory cytokines and parasitized RBCs [36-38], (g) which may result in autocrine ferroportin blocking. (h) In addition, inflammatory stimuli inhibit ferroportin and modulate cellular iron uptake by DMT-1 and transferrin receptor [36, 39]. As a consequence of these processes iron is sequestered in macrophages. (i) Salmonella enters the cell via endocytosis and proliferates in phagosomes. Nramp-1 expression is required to control Salmonella growth by depleting the phagosome of iron (c) [46]. In a co-infection, Salmonellae spp. may benefit from the increased cellular iron induced by a malaria infection and establish an infection. Whether both pathogens reside in the same macrophage during invasive NTS infection and malaria as depicted in the figure is unknown. Illustration by A. Kartikasari.

Figure 2. Systemic effects of malaria on body iron stores

(a) A schematic presentation of iron flows in normal circumstances. Hepcidin controls the amount of iron absorbed from the diet and the release of iron from macrophages from the reticulo-endothelial system [29]. There is a steady state of iron recycling from senescent RBCs that are degraded in macrophages into iron. This iron is transported via transferrin in the circulation towards the bone marrow where iron is essential for erythropoiesis. Body iron losses are minimal and not regulated. (b) Iron flows in malaria. During malaria infection the body iron homeostasis changes, but total amount of body iron remains similar as is visualized by the change in the size of boxes. Inflammatory factors increase hepcidin release [30, 33, 76, 77]. As a consequence, absorption of iron from the diet is impaired, iron is redistributed to macrophages, less iron is bound to transferrin and iron stores become depleted. Finally, the erythropoiesis is impaired, due to hepcidin-mediated iron restriction, in addition to malaria-specific inhibitory factors (e.g., cytokines, hemozoin) [71]. Also, a blood stage malaria infection is hallmarked by hemolysis and increased phagocytosis of parasitized and non infected RBCs, which also augments the macrophage iron content. As suggested, the increased iron availability in malaria could facilitate the growth and replication of Salmonellae spp. Abbreviation: EP, erythrophagocytosis.