HEME DYSREGULATION LINKS HEMOGLOBINOPATHIES TO VISCERAL LEISHMANIASIS SUSCEPTIBILITY

Abstract

Visceral leishmaniasis (VL) is a lethal neglected tropical disease caused by Leishmania donovani, a parasite that cannot synthesize heme and must scavenge it from the host. How host heme status shapes infection outcome has remained poorly understood. Here we demonstrate that host heme availability is a direct determinant of parasitemia and uncover a competitive heme acquisition axis between host and parasite, mediated by the mammalian heme importer HRG1/SLC48A1 and its parasite counterpart LHR1. We show that L. donovani maintains intracellular heme stores, a previously unrecognized adaptation to heme scarcity. In HRG1-deficient mice, altered heme homeostasis and cytokine profiles restrict parasite survival and replication. Conversely, the heme-replete environment of sickle cell disease markedly increases susceptibility to L. donovani infection. Together, these findings establish the HRG1-LHR1 axis as a functional determinant of VL outcome, position host heme status as a biomarker of disease susceptibility, and identify heme importers as candidate therapeutic targets.