L. (L.) amazonensis and L. (L.) infantum factors potentially involved in virulence and in the development of different clinical forms

• Grant number: 24/18560-7
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Beatriz Simonsen Stolf
• Grantee: Beatriz Simonsen Stolf
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Giuseppe Palmisano ; José Angelo Lauletta Lindoso ; Mayara Ingrid Sousa Lima ; Sandra Marcia Muxel
• Associated scholarship(s): 25/15452-1 - Generation of clones of Leishmania amazonensis and Leishmania infantum knockout, addback and overexpressor of the genes of interest, BP.TT

Abstract

Leishmaniases, diseases caused by several species of Leishmania, are endemic in more than 90 countries and have annual incidences superior to 1 million cases, affecting mainly socioeconomically vulnerable populations. Symptomatic infections may result in cutaneous, mucocutaneous or visceral clinical forms. In Brazil, the most common dermotropic species are L. (V.) braziliensis, L. (L.) amazonensis and L. (V.) guyanensis. Each of these species may cause more than one clinical manifestation, as is the case of L. (L.) amazonensis, which commonly leads to localized cutaneous leishmaniasis (LCL) but may eventually cause diffuse cutaneous leishmaniasis (DCL). This last manifestation is associated to anergy of the patient to Leishmania antigens and is an aggressive and hard to treat form. Visceral leishmaniasis in Brasil is usually caused by L. (L.) infantum. The clinical form of leishmaniasis results from characteristics of the Leishmania species and isolate and of the host.This project includes two subprojects, both focused on deciphering Leishmania components involved in virulence. In subproject 1 we will investigate factors involved in the virulence of clinical isolates of L. (L.) amazonensis recovered from LCL and DCL patients. We will compare infectivity in vitro and virulence (in vivo) in different mouse strains. We also intend to compare the genomes of selected isolates aiming to identify genes or genetic alterations potentially related to virulence profile and/or clinical manifestation. In the case we find a potential biomarker, we will validate its relevance by generating a mutant knockout parasite employing CRISPR/Cas9 or an overexpressing lineage. In subproject 2 we will analyze the importance of sialic acid (Sias) and of two genes potentially involved in Sias synthesis in L. (L.) infantum. Sias was functionally studied only in L. (L.) donovani, and nothing is known about its synthesis in Leishmania. We intend to generate mutants for two genes (enzymes) potentially involved in Sias pathway and to investigate their importance in parasite infectivity and virulence.The results obtained in subproject 1 will unravel the contribution of characteristics of L. (L.) amazonensis isolates for the development of LCL or DCL and for virulence. The results of subproject 2 will help understanding Sias synthesis pathway and the importance of this sugar in L. (L.) infantum. Our project will bring new information about molecules involved in infectivity and virulence of Leishmania species important in Brasil, which may eventually be explored as targets for drugs or vaccines. (AU)