Renal iron homeostasis tackles with glucose metabolism to confer disease tolerance in malaria infection

Project Information

RIGM

Grant agreement ID: 892773

DOI

10.3030/892773

Project closed

EC signature date 26 March 2020

Start date 1 June 2020

End date 31 May 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 147 815,04

EU contribution

€ 147 815,04

Coordinated by

FUNDACAO CALOUSTE GULBENKIAN
Portugal

Periodic Reporting for period 1 - RIGM (Renal iron homeostasis tackles with glucose metabolism to confer disease tolerance in malaria infection)

Reporting period: 2020-06-01 to 2022-05-31

Summary of the context and overall objectives of the project

Malaria is a top rank infectious disease worldwide caused by Plasmodium infection.
In RIGM, we proposed that the sole iron exporter ferroportin (encoded by Solute Carrier Family 40 Member 1, Slc40a1) promotes disease tolerance to malaria via renal iron control. We aimed to unravel potential crosstalk with renal ferroptosis cascade and glucose metabolism, dictated by SLC40A1.

Malaria is a heavy burden in developing countries. Together with other tropical infectious diseases, they are threatening the non-endemic regions due to climate change. RIGM sought to obtain knowledge directly related to the role of Slc40a1 in the establishment of disease tolerance in malaria. It should generate fundamental academic knowledge and provide potential therapeutic targets.

The main objective of RIGM was to identify and characterize the role of renal iron export by Slc40a1 in establishing disease tolerance to malaria, by using a combination of conditional/inducible gene deletion mouse models and Plasmodium infection model, to test iron export controls for the development of ferroptotic tissue damage and kidney gluconeogenesis during malaria.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

As we proceeded with the project, the data indicated a different direction. Therefore, we adapted our study to the new hypothesis.
We found a negative correlation between kidney injury biomarker (Blood urea, creatinine) concentrations with hemogram parameters in a malaria cohort with Plasmodium. falciparum infection. We employed a severe malarial anemia experimental model in mice by the administration (intraperitoneal, i.p.) of Plasmodium chabaudi chabaudi AS (Pcc)-infected RBC (i.e. infection). Iron content is redistributed among major organs.
Hereafter we characterized transcriptome in renal proximal tubule epithelial cells (RPTEC) from Pcc-infected mice vs non-infected control in Egfp-L10.Pepck mice. We identified Slc40a1 as one of the induced genes. We confirmed the induction of Slc40a1 mRNA and protein by Pcc-infection in whole kidneys and RPTEC. We generated Slc40a1PepckΔ/Δ mice and found that they were more sensitive to Pcc infection, as compared to control Slc40a1fl/fl mice. We found a hypometabolic response and lower hemogram parameters in Pcc infected Slc40a1PepckΔ/Δ vs. Slc40a1fl/fl mice. Iron accumulation in the kidneys increased in Pcc-infected Slc40a1PepckΔ/Δ vs. control Slc40a1fl/fl mice. The renal iron accumulation contributes to the pathogenesis of malarial acute kidney injury (AKI). We found that Pcc infection in Slc40a1PepckΔ/Δ mice was associated with a more pronounced induction of erythropoietin (Epo) signaling genes in the kidneys and spleen, compared to control Slc40a1fl/fl mice. Plasma from non-infected Slc40a1fl/fl or Slc40a1PepckΔ/Δ mice, but not plasma from Pcc-infected Slc40a1PepckΔ/Δ mice supported the differentiation of MEL cells into erythrocyte-like cells. This is associated with the higher iron concentration and non-transferrin-bound iron (NTBI) in plasma. Compensatory erythropoiesis was impaired, with a reduction in the intracellular iron (Fe2+) content. Transfusion of purified RBC fully protected Slc40a1PepckΔ/Δ mice from Pcc infection.

Results beyond the proposed work
I participated in understanding the hypometabolic status related to hepatic gluconeogenesis and its impact on the establishment of disease tolerance and participated in a study showing that ferritin heavy chain is essential to maintaining the peripheral Regulatory T cell population.

Exploitation and dissemination
The results of RIGM are still in line with the main hypothesis that iron export plays a role in establishing disease tolerance to malaria. Our data shed light on renal physiology in establishing disease tolerance to malaria and provides a novel way for the therapeutic investigation to protect kidney function and alleviate malarial anemia concomitantly.
Several publications and communications arose from work performed under RIGM, which are enumerated below. The results were presented in an internal scientific seminar at the IGC and were also presented online at one conference. The MSCA funding (RIGM) has been acknowledged in all the dissemination activities.

Preprint
• A Protective Inter-Organ Communication Response Against Life-Threatening Malarial Anemia. Qian Wu, Euclides Sacomboio, Lara Valente de Souza, Rui Martins, Jamil Kitoko, Sílvia Cardoso, Temitope W. Ademolue, Tiago Paixão, Jaakko Lehtimäki, Caren Norden, Pierre-Louis Tharaux, Guenter Weiss, Fudi Wang, Susana Ramos, and Miguel P. Soares. bioRxiv. doi: https://doi.org/10.1101/2022.01.12.475857. This paper is in an open access preprint server (bioRxiv)


Manuscripts under revision:
• Iron metabolism Controls Regulatory T Cell Function. Faouzi Braza*, Ana Rita Carlos*, Qian Wu*, Patricia Bastos-Amador*, Louise M Bergman, Jamil Kitoko, Eloy Cuadrado, Cristina Q Ameneiro, Brendon P Scicluna, Rui Martins, Wilson T. Ademolue, Mirko Peitzsch, Jorge Almeida-Santos, Jessica A. Thompson, Silvia Cardoso, Pedro Ventura, Vital Da Silva Domingues, Ines A Cabral, Sebastian Weis, Marco Groth, Miguel Fidalgo, Jocelyne Demengeot, Derk Amsen,and Miguel P. Soares. (This manuscript is under the first revision of Journal of Experimental Medicine).

• Renal Control of Life-Threatening Malarial Anemia. Qian Wu, Euclides Sacomboio, Lara Valente de Souza, Rui Martins, Jamil Kitoko, Sílvia Cardoso, Temitope W. Ademolue, Tiago Paixão, Jaakko Lehtimäki, Caren Norden, Pierre-Louis Tharaux, Guenter Weiss, Fudi Wang, Susana Ramos, and Miguel P. Soares. This manuscript is the same as indicated in the Preprint, submitted to Cell Reports on August 2nd, 2022. It is currently under peer review

Conference/seminar communications:
• A Protective Inter-Organ Communication Response Against Life-Threatening Malarial Anemia,
Qian Wu. EMBO | EMBL Symposium. Inter-organ communication in physiology and disease. Presented in poster as online event (2022.3.21-3.23)
• Kidney Iron dictates disease tolerance in malaria,
Qian Wu. IGC Internal Seminars – hosted by IGC, Portugal (2022.3.31)

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

RIGM aimed to discover basic and translational findings directly related to the role of Slc40a1 in establishing disease tolerance to malaria. Achievement should pave a pathway to developing new therapeutic targets against malaria, where the increasing emergence of drug resistance makes the modulation of disease tolerance an alternative yet promising therapeutic strategy. The translational aspect of RIGM bore the potential to decrease the rising disease burden of malaria directly and potentially other hemolytic diseases worldwide including in the European Union (EU), and generate fundamental academic knowledge as well as clinically relevant data, with potential benefits for the European economy and society in general. Taken together, RIGM has achieved significant scientific discoveries, which also provide the potential to directly alleviate the disease burden of malaria globally, and better prepare the EU to face possible future health risks. Especially, the beneficial effect of the knowledge derived from RIGM could improve malaria treatment and the fact that malaria, like other tropical diseases, is becoming a potential risk factor in non-endemic areas due to climate changes. Despite some derivations of the original proposal, RIGM should be a major milestone for my career development, supported by the generation of multiple scientific publications to secure funding from competitive sources.

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