A metabolic-based defense strategy against malaria

Objectif

Human diseases can emerge from evolutionary trade-offs, when the fitness advantage associated with natural selection of a trait is balanced out by another trait that reduces fitness. KILLBILL builds on this biological principle by reframing jaundice as an adaptive defense mechanism. Regarded historically as a symptom, we discovered that unconjugated bilirubin, the hallmark of jaundice, provides dual protection against malaria: it kills Plasmodium while shielding host tissues from ferroptosis, an iron-dependent cell death pathway causing organ damage. These salutary effects extend beyond malaria, towards sickle cell disease - an inherited hemolytic condition shaped by malaria. We hypothesize that bilirubin contributes to sickle hemoglobin's anti-malarial effect while protecting from hemolysis-induced pathology in sickle cell disease. KILLBILL will define the molecular logic of this dual protection with the potential to translate it into an evolution-informed therapeutic framework. This will be achieved through innovative experimental systems, encompassing genetically modified mice with controlled levels of jaundice and transgenic parasites reporting on bilirubin sensing to link bilirubin targeting with parasite outcomes. Multi-omics and computational modeling will map parasite and host bilirubin-responsive pathways, while proteome-wide assays and genetic manipulation will validate these functionally. We will zoom in the host, focusing on pathways whereby bilirubin regulates ferroptosis and anti-malaria immunity, probing how bilirubin contributes to the anti-malarial effect of sickle hemoglobin and validating ferroptosis as a therapeutic target in both malaria and sickle cell disease. KILLBILL explores bilirubin-responsive molecular vulnerabilities to deliver the blueprints for future dual-action therapeutic strategies reducing pathogen burden and protecting host tissues, towards evolution-informed drug discovery in malaria and beyond.