Ademolue, T. W. | bioRxiv Science

bioRxiv2022

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

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.

pathology↗

bioRxiv2021

A HYPOMETABOLIC DEFENSE STRATEGY AGAINST PLASMODIUM INFECTION

Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal presentation of Plasmodium falciparum infection of humans. Here we report that mice reduce blood glucose levels in response to Plasmodium infection via a coordinated response whereby labile heme, an alarmin produced via hemolysis, induces anorexia and represses hepatic glucose production (HGP). While protective against unfettered immune-mediated inflammation, organ damage and anemia, when sustained over time heme-driven repression of HGP can progress towards hypoglycemia, compromising host energy expenditure and thermoregulation. This hypometabolic state arrests the development of asexual stages of Plasmodium spp., which undergo pyknosis and develop mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program reducing its virulence and inducing sexual differentiation towards the production of transmissible gametocytes. We infer that malaria-associated hypoglycemia represents a trade-off of an evolutionarily conserved defense strategy restricting Plasmodium spp. from accessing host-derived glucose and balancing parasite virulence and transmission.

immunology↗