Study of the cross-regulation between transport of iron and heme mediated by LIT1 and LHR1 in Leishmania

• Grant number: 19/03861-3
• Support Opportunities: Scholarships in Brazil - Master
• Start date: July 01, 2019
• End date: August 31, 2021
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Maria Fernanda Laranjeira da Silva
• Grantee: Ahyun Hong
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/23933-3 - Identification and characterization of membrane proteins involved in iron transport and metabolism in Leishmania, AP.JP

Abstract

Leishmaniases are a spectrum of diseases caused by protozoan parasites of the genus Leishmania that affect millions of people around the world. Leishmania is transmitted to humans by the bite of infected phlebotomine sandflies. These organisms are digenetic parasites that during the intracellular phase of their life cycle are called amastigotes. The amastigote form inhabits the parasitophorous vacuoles of the mammalian macrophages. The processes leading to the differentiation of the promastigotes form, found in the insect vector, to the amastigotes form are the subject of many studies since the amastigotes can survive and replicate inside of macrophages despite their cell defense arsenal. One of the conditions observed in the macrophage parasitophorous vacuole is the lack of essential nutrients, such as iron and heme. In particular, Leishmania are heme auxotrophs, hence the acquisition of heme is essential for parasite survival and replication. Previous studies have unveiled several pathways of iron and heme transport and metabolism in Leishmania. LIT1 (Leishmania Iron Transporter 1) was shown to mediate iron uptake and LHR1 (Leishmania Heme Response 1) was shown to mediate heme acquisition. Both were shown to be crucial for parasite growth and replication in macrophages, since knockout of a single LHR1 allele (LHR1 SKO) or both LIT1 alleles (LIT1 KO) had a significant impact on parasite in vitro and in vivo replication in vivo. However, these studies did not elucidate how these pathways are inter-regulated. Thus, the aim of this project is to investigate the cross-regulation between these iron and heme transporters by evaluating gene expression, iron and heme intracellular content, and virulence of LHR1 SKO and LIT1 KO L. amazonensis strains overexpressing LIT1 and LHR1, respectively. Identification of the regulatory mechanisms and pathways related to iron and heme acquisition are critical for a better understanding of Leishmania physiology and the host-pathogen interaction. (AU)