Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria; Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
Rui Martins
Instituto Gulbenkian de Ciência, Oeiras, Portugal
Jamil Kitoko
Instituto Gulbenkian de Ciência, Oeiras, Portugal
Sílvia Cardoso
Instituto Gulbenkian de Ciência, Oeiras, Portugal
Temitope W. Ademolue
Instituto Gulbenkian de Ciência, Oeiras, Portugal
Tiago Paixão
Instituto Gulbenkian de Ciência, Oeiras, Portugal
Jaakko Lehtimäki
Instituto Gulbenkian de Ciência, Oeiras, Portugal
Ana Figueiredo
Instituto Gulbenkian de Ciência, Oeiras, Portugal
Caren Norden
Instituto Gulbenkian de Ciência, Oeiras, Portugal
Pierre-Louis Tharaux
Paris Cardiovascular Center (PARCC), Institut National de la Santé et de la Recherche Médicale (Inserm), Université Paris Cité, Paris, France
Guenter Weiss
Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria; Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
Fudi Wang
The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
Susana Ramos
Instituto Gulbenkian de Ciência, Oeiras, Portugal; Corresponding author
Miguel P. Soares
Instituto Gulbenkian de Ciência, Oeiras, Portugal; Corresponding author
Summary: Iron recycling prevents the development of anemia under homeostatic conditions. Whether iron recycling was co-opted as a defense strategy to prevent the development of anemia in response to infection is unclear. We find that in severe Plasmodium falciparum malaria, the onset of life-threatening anemia is associated with acute kidney injury (AKI), irrespective of parasite load. Using a well-established experimental rodent model of malaria anemia, we identify a transcriptional response that endows renal proximal tubule epithelial cells (RPTECs) with the capacity to store and recycle iron during P. chabaudi chabaudi (Pcc) infection. This response encompasses the induction of ferroportin 1/SLC40A1, which exports iron from RPTECs and counteracts AKI while supporting compensatory erythropoiesis and preventing the onset of life-threatening malarial anemia. Iron recycling by myeloid cells is dispensable to this protective response, suggesting that RPTECs provide an iron-recycling salvage pathway that prevents the pathogenesis of life-threatening malarial anemia.
