Dynamic control of hepatic Plasmodium numbers by hepcidin despite elevated liver iron during iron supplementation

Abstract

Treatment of iron deficiency anemia in malaria endemic areas is complicated as iron supplementation increases malaria risk while malaria decreases iron absorption. Here we measured the influence of hepcidin expression and nonheme iron during iron supplementation on hepatic Plasmodium berghei numbers in anemic and nonanemic mice. Despite elevated hepatic nonheme iron on the high iron diet, elevated hepcidin expression is associated with less parasite bioavailable iron and lower hepatic parasite loads in anemic, iron deficient mice after both two and six weeks of supplementation. A marginal trend to lower parasite hepatic numbers was seen in nonanemic, iron replete mice. In a transgenic model of severe anemia, mice with a deletion in Sec15l1, which reportedly have normal liver iron and normal hepcidin expression, there were no changes in liver parasite numbers or bloodstage numbers or outcome in the lethal P. yoelii model. In summary during iron supplementation the lower hepatic malaria numbers are regulated more by hepcidin than the absolute level of nonheme hepatic iron.

Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

“…Although the exact mechanisms are unclear, P. berghei liver-stage development is influenced by host iron homeostasis 3233. Recently, a vacuolar iron transporter was described that plays an important (although not critical) role during liver infection in vivo and in vitro 34.…”

“…Evidence is mounting that transport processes of metal ions, in particular of heavy metals such as iron, copper, and zinc, could provide efficient targets for chemoprophylactic treatments. Although the exact mechanisms are unclear, P. berghei liver-stage development is influenced by host iron homeostasis 32 33 . Recently, a vacuolar iron transporter was described that plays an important (although not critical) role during liver infection in vivo and in vitro 34 .…”

A vacuolar iron-transporter homologue acts as a detoxifier in Plasmodium

“…Iron withdrawal by the use of iron chelators has been explored as an antimalarial approach for decades 27 and novel compounds with improved pharmacokinetic properties are being investigated 23 24 . During infection, growth of malaria parasites is influenced by the host iron status both in liver 25 28 and blood 29 . P. falciparum growth is reduced in iron-deficient erythrocytes while iron supplementation eliminates this growth attenuation 30 .…”

Elimination of Hepatic Rodent Plasmodium Parasites by Amino Acid Supplementation

“…Recently, dietary alterations have been shown to significantly alter the capacity of Plasmodium, the malaria parasite, to replicate in the blood of its mammalian host, altering the clinical outcome of infection ( Shankar, 2000 , Clinton Health Access Initiative, 2016 , Caulfield et al., 2004 , (MSF), 2013 , Nyariki et al., 2019 ; Qin et al., 2019 ; Wu et al., 2018 ; Castberg et al., 2018 ; Goheen et al., 2017 ; Awasthi et al., 2017 ; Alkaitis and Ackerman, 2016 ; Meadows et al., 2015 ; Kirk and Saliba, 2007 ; Mancio-Silva et al., 2017 ; Counihan et al., 2017 ). Less is known about the impact of dietary alterations on the capacity of this parasite to complete the initial stage of its mammalian infection in the liver, and on how targeted modifications of nutritional availability can be employed as infection control tools ( Vreden et al., 1995 ; Zuzarte-Luis et al., 2017 ; Goma et al., 1996 ; Ferrer et al., 2016 ). This study aimed at establishing a dietary supplementation that could be used to modulate the establishment of a hepatic infection by Plasmodium parasites.…”

“…Interestingly, iron supplementation has yielded contradictory results in what concerns its impact on Plasmodium liver infection. While one study has suggested that it promotes hepatic parasite development ( Goma et al., 1996 ), another, more recent, study reported a hepcidin-dependent decrease in hepatic parasite numbers following iron supplementation ( Ferrer et al., 2016 ). Thus, a more comprehensive understanding on the impact of dietary alterations on the liver stage of Plasmodium infection is clearly warranted.…”