Localized Leishmania major infection causes systemic iron deficiency that can be controlled by oral iron supplementation

Abstract

Leishmania major (L. major) and its related parasitic species infection causes human cutaneous leishmaniasis that results into disfiguring skin lesion. Although L. major infection has been found to alter macrophage iron homeostasis we have limited understanding on whether it can also manipulate the same at systemic level. In fact, localized L. major infection found to promote iron deficiency anemia in children by an unknown mechanism. To address these unresolved issues, Balb/c mouse were infected with L. major and iron status in different organs were monitored systematically with the development of cutaneous lesion. At week 10 post infection when there was maximum lesion development in the parasite infected left hind footpad, the iron content increased significantly in this tissue with the concomitant increase in parasite burden. L. major infection mediated iron accumulation in infected mouse footpad was found to be due to transferrin receptor upregulation and natural resistance-associated macrophage protein 1 (Nramp1) downregulation. Surge in iron level was found to be associated with the reduced hepatic iron storage that resulted increased serum iron. Limited iron storage in liver and bone-marrow of infected mice caused reduced hemoglobin level and production of deformed erythrocytes. Interestingly, L. major infected mice developed splenomegaly with significant upregulation of erythroid related genes. Importantly, oral iron supplementation post infection rescued the development of cutaneous lesion in infected mice. Together, our study unravelled a comprehensive mechanism behind developing iron deficiency anemia during cutaneous leishmaniasis and a novel therapeutic route of treating this infection by delivering iron.