Hemoglobin Endocytosis and Intracellular Trafficking: A Novel Way of Heme Acquisition by Leishmania

Abstract

Leishmania species are causative agents of human leishmaniasis, affecting 12 million people annually. Drugs available for leishmaniasis are toxic, and no vaccine is available. Thus, the major thrust is to identify new therapeutic targets. Leishmania is an auxotroph for heme and must acquire heme from the host for its survival. Thus, the major focus has been to understand the heme acquisition process by the parasites in the last few decades. It is conceivable that the parasite is possibly obtaining heme from host hemoprotein, as free heme is not available in the host. Current understanding indicates that Leishmania internalizes hemoglobin (Hb) through a specific receptor by a clathrin-mediated endocytic process and targets it to the parasite lysosomes via the Rab5 and Rab7 regulated endocytic pathway, where it is degraded to generate intracellular heme that is used by the parasite. Subsequently, intra-lysosomal heme is initially transported to the cytosol and is finally delivered to the mitochondria via different heme transporters. Studies using different null mutant parasites showed that these receptors and transporters are essential for the survival of the parasite. Thus, the heme acquisition process in Leishmania may be exploited for the development of novel therapeutics.

Continuous endosomes form functional subdomains and orchestrate rapid membrane trafficking in trypanosomes

“…In the single-celled parasite Giardia , the peripheral vesicles that constitute the endosomal organelles form an ‘interconnected network’ (reviewed in Benchimol and de Souza, 2022 ), while the endosome-like compartment in Toxoplasma is likely involved in both endocytic and exocytic trafficking (reviewed in McGovern et al, 2021 ). In Leishmania, the endosomal system has not been fully characterized but seems to be under physical tension (reviewed in Ansari et al, 2022 ). Thus, parasitic protozoa might feature interesting variations of the common cell biological process of endocytosis.…”

Leishmania highjack host lipid body for its proliferation in macrophages by overexpressing host Rab18 and TRAPPC9 by downregulating miR-1914-3p expression

“…Thus, the major thrust is to identify new chemotherapeutic targets against Leishmania. Leishmania do not have fully characterized biosynthetic pathways for heme [32,33], purine [34], folate [35], fatty acids [36][37][38] and depend on the host to scavenge these nutrients for their intracellular survival [39][40][41][42]. Thus, understanding the mechanism of acquisition of essential nutrient like fatty acids, heme, folate etc.…”

Continuous endosomes form functional subdomains and orchestrate rapid membrane trafficking in trypanosomes

“…In the single-celled parasite Giardia, the peripheral vesicles that constitute the endosomal organelles form an "interconnected network" (reviewed in Benchimol and de Souza, 2022), while the endosome-like compartment in Toxoplasma is likely involved in both endocytic and exocytic trafficking (reviewed in McGovern et al, 2021). In Leishmania, the endosomal system has not been fully characterized but seems to be under physical tension (reviewed in Ansari et al, 2022). Thus, parasitic protozoa might feature interesting variations of the common cell biological process of endocytosis.…”