Study of the regulation of iron and heme transporters at the Leishmania-host interface: effect of iron deficiency anemia on the virulence of Leishmania (L.) amazonensis.

Author(s)

Ahyun Hong

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB)
• Defense date: 2024-04-29

Examining board members

Maria Fernanda Laranjeira da Silva; Adriano Cappellazzo Coelho; Daniel José Galafasse Lahr; Roberto Kopke Salinas

• Advisor: Maria Fernanda Laranjeira da Silva

Abstract

Leishmaniasis, a disease caused by protozoan parasites of the genus Leishmania, affects millions of people around the world. Nutrient availability within parasitophorous vacuoles profoundly influences parasite replication and virulence during infection. Leishmania faces the challenge of acquiring essential nutrients, particularly iron and heme, from the host, as it lacks iron storage proteins and heme biosynthesis capacity. The acquisition is vital for survival, despite the cytotoxic potential of iron and heme. This project explored deep into the intricate regulatory mechanisms governing iron and heme transporters at the Leishmania-host interface. Challenges encountered during the validation of LIT1 mutant prompted a shift to CRISPR/Cas9 genome editing, stressing the genomic plasticity challenges of Leishmania. Phenotypic characterization of LIT1 and LHR1 overexpressors unraveled insights into the interplay between iron, heme, and Leishmania pathogenesis. While knockout mutants exhibited compromised replication in normal conditions, overexpression restored growth in heme-depleted media. Notably, LIT1 proved essential for intracellular replication, supported by in vivo infection showing delayed lesion development in LIT1 PKO mutants. The broader significance of the study goes beyond advancing our comprehension of host-parasite interactions in leishmaniases, highlighting the crucial influence of the host\'s iron and heme status on disease progression. Additionally, the identification of potential chemotherapeutic targets not only offers new directions for ongoing exploration in this field but also holds promise for the development of innovative strategies to combat leishmaniases and enhance treatment outcomes. (AU)

• FAPESP's process: 21/03355-0 - Study of the regulation of iron and heme transporters at the Leishmania-host interface: effect of iron deficiency anemia on the virulence of Leishmania (L.) amazonensis
• Grantee: Ahyun Hong
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)