ALTERATION OF IRON HOMEOSTASIS IN A MOUSE MODEL OF LIVER-STAGE PLASMODIUM INFECTION
Author(s): ,
Francesca Vinchi
Affiliations:
Iron Research Program,New York Blood Center,New York,United States
,
Richard Sparla
Affiliations:
Iron Homeostasis Group,University Hospital Heidelberg,Heidelberg,Germany
,
Cheryl Lobo
Affiliations:
Blood-Borne Parasites Lab,New York Blood Center,New York,United States
Martina Muckenthaler
Affiliations:
Iron Homeostasis Group,University Hospital Heidelberg,Heidelberg,Germany
EHA Library. Vinchi F. Jun 15, 2019; 267439; S856
Dr. Francesca Vinchi
Dr. Francesca Vinchi
Contributions
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Abstract

Abstract: S856

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 12:30 - 12:45

Location: Amtrium

Background
 

Malaria, a major health challenge in developing countries, is a hemolytic disorder causing anemia in infected subjects. The most severe complications associated with malaria include cerebral symptoms, frequently leading to death. Patients who survive commonly face anemia due to parasite-induced hemolysis of red blood cells. During malaria infections, iron plays a critical role in both promoting parasite proliferation and in supporting erythropoietic demand.

Aims
Iron-related parameters so far have been studied in mouse models of blood-stage malaria but not in models of liver-stage infection.

Methods

Here we applied a mouse model of liver-stage Plasmodium infection, triggered by intravenous injection of Plasmodium parasites. We used different Plasmodium strains (P.Berghei Anka, P.Bergei NK65) which cause various levels of parasitemia, hemolysis and inflammation. This model shows the advantage of closely mimicking the pathophysiology of human malaria infection, which starts with liver invasion by Plasmodium parasites.

Results

Mice infected with both strains develop anemia 7 days after parasite injection, which severely worsens up to 17 days. The anemic phenotype is accompanied by a strong increase in circulating erythropoietin (EPO) levels, enhanced duodenal iron absorption and elevated serum iron and NTBI levels. We show that plasma hepcidin levels are reduced, and Erythroferrone (ERFE) and GDF15 mRNA levels are increased in bone marrow and spleen of Plasmodium infected mice in a time-dependent manner. These observations suggest that the erythroid regulators suppress hepcidin levels despite the significant increase in circulating IL-6 levels. Importantly circulating hepcidin levels show a direct correlation with hemoglobin levels and an inverse correlation with EPO levels and ERFE expression in the bone marrow As a consequence of severe hemolysis and increased iron absorption, tissue iron deposition (liver, spleen, brain, kidney) is strongly elevated.

Conclusion

These findings importantly show that liver-stage Plasmodium infection in mice models alterations in iron homeostasis occurring during the disease and can be used to study iron metabolism as a valuable model that more closely reflects what happens in human malaria. Our results highlight a role for hepcidin, ERFE and GDF15 in the alteration of iron homeostasis observed in liver-stage Plasmodium infection. We suggest that the modulation of these parameters might ameliorate anemia, iron burden and parasitemia during Plasmodium infection.

Session topic: 29. Iron metabolism, deficiency and overload

Keyword(s): Iron overload

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