Unraveling the regulatory mechanisms of host-parasite interaction of Leishmania: focus on post-transcriptional and post-translational changes

• Grant number: 22/03075-0
• Support Opportunities: Research Grants - Initial Project
• Start date: February 01, 2023
• End date: January 31, 2028
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Nilmar Silvio Moretti
• Grantee: Nilmar Silvio Moretti
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Antonio Mauro Rezende ; Clara Lúcia Barbiéri Mestriner ; Elton José Rosas de Vasconcelos ; Igor dos Santos Cestari ; Katlin Brauer Massirer ; Marcelo Ribeiro da Silva Briones ; Niels Olsen Saraiva Câmara ; Patricia Xander Batista ; Rafael de Freitas e Silva ; Rubens Lima do Monte Neto ; Tiago Rodrigues Ferreira
• Associated research grant(s): 22/14226-0 - Spatial transcriptomics to uncover spatio-temporal expression dynamics during Leishmania host-parasite interactions, AP.R SPRINT
• Associated scholarship(s): 25/20402-3 - Exploring nuclear plasticity and chromatin structure in Leishmania, BP.DR; 25/06986-2 - ImuneAcetyLeish: Investigating regulatory mechanisms of protein acetylation in Leishmania-host interaction, BP.PD; 25/06837-7 - Epimune: Investigating epitranscriptomic alterations in Leishmania-host interaction, BP.DR; + associated scholarships 25/06325-6 - Investigating the role of m6A in the biology and stress response of Leishmania, BP.DR; 25/03898-5 - Unraveling the role of YEATS domains in the cell cycle and DNA repair of Leishmania mexicana, BP.MS; 23/02323-3 - Biochemical and functional characterization of NAT10 enzyme from Leishmania, BP.MS; 23/02341-1 - Study of the involvement of RNA modifications during the Leishmania parasite-host interaction, BP.MS - associated scholarships

Abstract

The life cycle of species of the genus Leishmania is complex and involves flagellated promastigote forms present in the sandfly vector and amastigote forms present inside the macrophages of the mammalian host. During the transition from one host to another, the parasite encounters different environmental conditions that lead to changes in its gene expression, protein synthesis, metabolism and morphology for its survival and multiplication. The mechanisms that allow Leishmania to adapt to this transition are still poorly understood. One hypothesis is that the parasite uses RNA post-transcriptional and protein post-translational modifications to regulate gene expression/protein synthesis and the function of key proteins involved in its differentiation. Another important factor during the Leishmania life cycle is how the parasite manages to escape the macrophages' defense mechanisms during infection. Some aspects of this life-cycle step have already been investigated and point to changes in the levels of chromatin acetylation and the expression of specific macrophage genes. Thus, in this project we will have two focus of investigation: one on the parasite and how the acetylation of RNA (ac4C) and proteins can affect the processes that are important for Leishmania stage differentiation; and another focused on the host cell and how Leishmania infection can lead to RNA and protein modifications in the macrophage, affecting the immune response against the parasite. For this, we will investigate the role: 1) of ac4C RNA modification in the Leishmania stages differentiation; 2) of protein acetylation in the parasite stages differentiation, using the lysine deacetylases (KDACs) as a study model; 3) of protein acetylation in macrophages during Leishmania infection, focusing on the host cell KDACs and their role in the immune response; 4) of m6A RNA modification in the host cell during Leishmania infection, and how this process impacts the parasite proliferation. The investigation of these mechanisms will lead to a deeper understanding of the biology of Leishmania during its life cycle and will map new processes that may constitute potential targets for new drugs in the control of leishmaniasis. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

RODOLPHO, B. T.; BERTAGNA, N. B.; FAVORETTO, C. A.; MORETTI, N. S.; CRUZ, F. C.. Maternal separation stress increases alcohol preference regardless of DNA methylation and histone acetylation or methylation in the amygdala. Physiology & Behavior, v. 291, p. 7-pg., 2025-03-15. (20/04389-3, 20/01331-4, 19/24073-3, 22/03075-0)

SILVA, RAFAEL DE FREITAS E; BASSI, GABRIELA; CAMARA, NIELS OLSEN SARAIVA; MORETTI, NILMAR SILVIO. Sirtuins: Key pieces in the host response to pathogens' puzzle. Molecular Immunology, v. 160, p. 11-pg., 2023-07-10. (18/09948-0, 20/07870-4, 22/03075-0)

WASSANO, NATALIA S.; DA SILVA, GABRIELA B.; REIS, ARTUR H.; GERHARDT, JAQUELINE A.; ANTONIEL, EVERTON P.; AKIYAMA, DANIEL; REZENDE, CAROLINE P.; NEVES, LEANDRO X.; VASCONCELOS, ELTON J. R.; DE FIGUEIREDO, FERNANDA L.; et al. Sirtuin E deacetylase is required for full virulence of Aspergillus fumigatus. COMMUNICATIONS BIOLOGY, v. 7, n. 1, p. 17-pg., 2024-06-08. (18/09948-0, 20/06151-4, 22/03075-0, 21/04977-5, 22/02992-0, 22/05731-2)

ALCANTARA, LAURA; FRANCO, CAIO; MORETTI, NILMAR; PILGER, DENISE. Editorial: Drug discovery for emerging and neglected tropical diseases: advances, challenges and perspectives. FRONTIERS IN DRUG DISCOVERY, v. 3, p. 3-pg., 2023-12-08. (22/03075-0)

BEZERRA, ANGELA MOREIRA; LEITE, ARIELY BARBOSA; REIS, CHRISTIAN ROBSON DE SOUZA; PITTA, JOAO LUIZ DE LEMOS PADILHA; MARAN, SUELLEN RODRIGUES; MORETTI, NILMAR SILVIO; MOURA, DANIELLE MARIA NASCIMENTO; REZENDE, ANTONIO MAURO. Impact on the Leishmania mexicana transcriptome due to knockout of genes encoding orthologs of methyltransferases involved in m1A and m5C mRNA modifications. PARASITES & VECTORS, v. 18, n. 1, p. 18-pg., 2025-07-31. (23/16672-0, 22/03075-0, 18/09948-0, 21/13477-6)