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(se abrirá en una nueva ventana). 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)
