P1491: the dynamic interaction between inflammation and the iron sensor hfe, in severe malaria-induced anemia

Topic: 29. Iron metabolism, deficiency and overload Background: Severe malarial anemia (SMA) is a complication developed during Plasmodium infection. It is often associated with increased rates of malaria-related morbidity and mortality, especially in children and pregnant women. Hence, it is fundamental to investigate new parameters to prevent this lethality. The occurrence of ineffective erythropoiesis, caused by a dysregulated erythropoietin (EPO)-erythropoietin receptor (EPOR) signaling pathway, is one of the main features of SMA. Aims: Therefore, to gain new insights into the pathogenesis of SMA and to better understand the dynamic interaction between erythropoiesis and inflammation, wild-type and HFE knockout mice were injected with Plasmodium chabaudi chabaudi (Pcc). Methods: Due to the fundamental role of iron in erythropoiesis and immune response activation, the expression of iron sensors, like HFE, was analyzed, detecting a strict correlation with disease severity. With this in mind, the action of HFE in the pathogenesis of SMA and its role on the immune response activation, elicited to combat malaria, was also investigated, and compared to Pcc-infected wild-type animals. Results: Results suggested that the anemic profile, associated with malaria infection, improves in Pcc-induced HFE knockout mice. However, an increased level of pro-inflammatory markers, such as CXCL1, IL-10, and TNF-α, was observed in these animals upon infection, when compared to wild type. The number and activation of peripheral blood leukocytes was assessed by flow cytometry. A higher activation of the immune response was found in HFE-deficient mice in relation to Pcc-induced wild type animals, especially in the first days of infection. The splenomegaly presented by HFE-deficient mice was linked to an enhanced inflammation, which persists along the infection, as demonstrated by the inflammatory profile of analyzed cells. Whether the improved anemia could be caused by a stronger immune response activation of Pcc-induced HFE-knockout mice in relation to wild-type animals, which is coupled to lower parasite counts in the blood, is likely the case. Summary/Conclusion: These findings suggest a potential role for HFE in the pathogenesis of SMA, revealing HFE as a potential target for therapeutic strategies against hemolytic disorders. Keywords: Anemia, Malaria, Inflammation, Infection