This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features!
Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log in
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 May;29(5):220-7.
doi: 10.1016/j.pt.201303006. Epub 2013 Apr 16.

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

Affiliations

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

Susanne van Santen et al. Trends Parasitol. 2013 May.

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.

PubMed Disclaimer

Figures

Figure 1
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
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.

References

    1. Morpeth SC, et al. Invasive non-typhi Salmonella disease in Africa. Clin Infect Dis. 2009;49:606–611. - PMC - PubMed
    1. Feasey NA, et al. Invasive non-typhoidal Salmonella disease: an emerging and neglected tropical disease in Africa. Lancet. 2012;379:2489–2499. - PMC - PubMed
    1. Hay SI, et al. A world malaria map: Plasmodium falciparum endemicity in 2007. PLoS Med. 2007;6:e1000048. - PMC - PubMed
    1. McLean E, et al. Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993-2005. Public Health Nutr. 2009;12:444–454. - PubMed
    1. Sazawal S, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet. 2006;367:133–143. - PubMed

Publication types

MeSH terms

Full text links
Elsevier Science full text link Elsevier Science Free PMC article
Cite

AltStyle によって変換されたページ (->オリジナル) /