A Protective Inter-Organ Communication Response Against Life-Threatening Malarial Anemia

Wu, Q.; Sacomboio, E.; Souza, L. V.; Martins, R.; Cardoso, S.; Ademolue, T. W.; Paixao, T.; Lehtimaki, J.; Norden, C.; Tharaux, P.-L.; Weiss, G.; Wang, F.; Ramos, S.; Soares, M. P.

doi:10.1101/2022.01.12.475857

bioRxiv · 10.1101/2022.01.12.475857

A Protective Inter-Organ Communication Response Against Life-Threatening Malarial Anemia

Wu, Q.·Sacomboio, E.·Souza, L. V.·Martins, R.·Cardoso, S.·Ademolue, T. W.·Paixao, T.·Lehtimaki, J.·Norden, C.·Tharaux, P.-L.·Weiss, G.·Wang, F.·Ramos, S.·Soares, M. P.

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Abstract

Anemia is a clinical hallmark and independent risk factor of malaria mortality, the disease caused by Plasmodium spp. infection. While malarial anemia arises from parasite-induced hemolysis, whether and how host metabolic adaptation to malaria regulates anemia severity is less understood. Here we demonstrate that reprogramming of organismal iron (Fe) metabolism by the kidneys is a central component of the host metabolic response regulating the pathogenesis of life-threatening malarial anemia. Renal proximal tubule epithelial cells (RPTEC) are the main cell compartment responsible for Fe storage and recycling during Plasmodium infection in mice. Transcriptional reprogramming of RPTEC couples immune resistance to Plasmodium infection to renal Fe export via the induction of the cellular Fe exporter SLC40A1/ferroportin 1. This integrated defense strategy is essential to deliver Fe to erythroblasts and support compensatory erythropoiesis to prevent the development of life-threatening anemia. Failure to mobilize Fe from RPTEC causes acute kidney injury (AKI) and is associated with life-threatening anemia in P. falciparum-infected individuals. These findings reveal an unexpected role of the kidneys in the control of organismal Fe metabolism and anemia severity during malaria.

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Wu, Q., Sacomboio, E., Souza, L. V., Martins, R., Cardoso, S., Ademolue, T. W., Paixao, T., Lehtimaki, J., Norden, C., Tharaux, P.-L., Weiss, G., Wang, F., Ramos, S., Soares, M. P.. 2022-01-12. A Protective Inter-Organ Communication Response Against Life-Threatening Malarial Anemia. https://doi.org/10.1101/2022.01.12.475857

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