The role of fatty acid-binding proteins in the macrophage infection by Leishmania: a potential target for new drugs against leishmaniasis

• Grant number: 14/21129-4
• Support Opportunities: Research Grants - Young Investigators Grants
• Duration: July 01, 2015 - November 30, 2020
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Danilo Ciccone Miguel
• Grantee: Danilo Ciccone Miguel
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Renato Arruda Mortara ; Selma Giorgio
• Associated scholarship(s): 18/07306-1 - Relation between fatty acid binding protein 4 and the biology of macrophagic vacuoles harboring Leishmania, BP.MS; 17/06542-0 - Functional evaluation of fatty acid binding protein 4 (FABP4) and PPAR-gamma modulation in Leishmania amazonensis, BP.MS; 15/26408-1 - Evaluation of the activity of macrophage FABP4 inhibitors in Leishmania infections, BP.IC; 15/17902-2 - Modulation of fatty acid-binding protein 4 (FABP4) levels in macrophages infected with Leishmania spp., BP.MS

Abstract

Leishmaniasis is an infection caused by protozoa of the genus Leishmania. While parasitizing the vertebrate host, amastigote forms occupy the parasitophorous vacuole of macrophages. Although the factors that ensure parasite survival in this microenvironment are poorly understood, it has been recently proposed that amastigotes incorporate fatty acids for amino acid biosynthesis in a very efficient way. Therefore, it is reasonable to assume the existence of a mechanism that controls the traffic of fatty acids in infected macrophages. It is known that fatty acid-binding proteins (FABPs), abundant in the cytoplasm of macrophages and adipocytes, transport fatty acids to different cell compartments and play a crucial role in the regulation of cellular metabolism and inflammatory response. Besides, recent studies have demonstrated that macrophage FABP type 4 (FABP4) transcript levels are increased after Leishmania infection. Based on these findings, this project aims to determine whether different Leishmania species of national epidemiological importance are capable of modulating the activity of the host cell FABP4, as an adaptive strategy to ensure access to nutrients and survival. Biochemical and molecular tools, such as FABP4 knockdown and treatment with FABP4 inhibitors, combined with transgenic mice infections, will allow the characterization of the FABP4 role during macrophage infection with Leishmania. Later, leishmanicidal effect of molecules capable of interfering with the cell signaling pathway mediated by the FABPs will be evaluated in an attempt to identify a drug candidate for leishmaniasis treatment. (AU)

Scientific publications

(11)

(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)

DA ROCHA SILVA, FLAVIA BENINI; MIGUEL, DANILO CICCONE; MACHADO, VICENTE ESTEVAM; CRUZ OLIVEIRA, WANDERSON HENRIQUE; GOULART, THAIS MARCHI; TOSTA, CHRISTIANN DAVIS; PINHEIRO, HILDETE PRISCO; PINTO, MARA CRISTINA. Influence of Leishmania (Viannia) braziliensis infection on the attractiveness of BALB/c mice to Nyssomyia neivai (Diptera: Psychodidae). PLoS One, v. 14, n. 4, APR 1 2019. (12/23832-9, 14/21129-4, 15/21100-9)

OLIVEIRA, ROSIMEIRE N.; CORREA, SHEILA A. P.; VIEIRA, KAREN M.; MENDES, TIAGO; ALLEGRETTI, SILMARA M.; MIGUEL, DANILO C.. In vitro schistosomicidal activity of tamoxifen and its effectiveness in a murine model of schistosomiasis at a single dose. Parasitology Research, v. 118, n. 5, p. 1625-1631, MAY 2019. (16/07137-0, 14/21129-4)

BORBA, JOYCE V. B.; SILVA, ARTHUR C.; RAMOS, PABLO I. P.; GRAZZIA, NATHALIA; MIGUEL, DANILO C.; MURATOV, EUGENE N.; FURNHAM, NICHOLAS; ANDRADE, CAROLINA H.. Unveiling the Kinomes of Leishmania infantum and L. braziliensis Empowers the Discovery of New Kinase Targets and Antileishmanial Compounds. COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL, v. 17, p. 352-361, 2019. (14/21129-4)

GRAZZIA, NATHALIA; BOAVENTURA, JR., SINESIO; GARCIA, VERA LUCIA; GADELHA, FERNANDA R.; MIGUEL, DANILO C.. Dihydroartemisinin, an active metabolite of artemisinin, interferes with Leishmania braziliensis mitochondrial bioenergetics and survival. Parasitology Research, v. 120, n. 2, JAN 2021. (14/21129-4)

ROSA, LETICIA B.; AIRES, ROCHANNA L.; OLIVEIRA, LAIANE S.; FONTES, JOSIELLE V.; MIGUEL, DANILO C.; ABBEHAUSEN, CAMILLA. A ``Golden Age{''} for the discovery of new antileishmanial agents: Current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system. CHEMMEDCHEM, v. 16, n. 11, MAR 2021. (19/16904-2, 18/21120-8, 14/21129-4)

MENDES, BRUNO; MINORI, KAREN; CONSONNI, SILVIO R.; ANDREWS, NORMA W.; MIGUEL, DANILO C.. ausative Agents of American Tegumentary Leishmaniasis Are Able to Infect 3T3-L1 Adipocytes In Vitr. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 12, FEB 4 2022. (15/17902-2, 14/21129-4, 17/21720-2)

ALCANTARA, LAURA M.; FERREIRA, THALITA C. S.; GADELHA, FERNANDA R.; MIGUEL, DANILO C.. Challenges in drug discovery targeting TriTryp diseases with an emphasis on leishmaniasis. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 8, n. 3, p. 430-439, DEC 2018. (15/24595-9, 14/21129-4, 15/10436-6)

MENDES, BRUNO; ALMEIDA, JOSE R.; VALE, NUNO; GOMES, PAULA; GADELHA, FERNANDA R.; DA SILVA, SAULO L.; MIGUEL, DANILO C.. Potential use of 13-mer peptides based on phospholipase and oligoarginine as leishmanicidal agents. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY, v. 226, DEC 2019. (14/21129-4)

PENA-CARRILLO, MARIA S.; PINOS-TAMAYO, EDGAR A.; MENDES, BRUNO; DOMINGUEZ-BORBOR, CRISTOBAL; PROANO-BOLANOS, CAROLINA; MIGUEL, DANILO C.; ALMEIDA, JOSE R.. Dissection of phospholipases A(2) reveals multifaceted peptides targeting cancer cells, Leishmania and bacteria. BIOORGANIC CHEMISTRY, v. 114, SEP 2021. (14/21129-4)

PARRA, LIZBETH L. L.; BERTONHA, ARIANE F.; SEVERO, IVAN R. M.; AGUIAR, ANNA C. C.; DE SOUZA, GUILHERME E.; OLIVA, GLAUCIUS; GUIDO, RAFAEL V. C.; GRAZZIA, NATHALIA; COSTA, TABATA R.; MIGUEL, DANILO C.; et al. Isolation, Derivative Synthesis, and Structure-Activity Relationships of Antiparasitic Bromopyrrole Alkaloids from the Marine Sponge Tedania brasiliensis. Journal of Natural Products, v. 81, n. 1, p. 188-202, JAN 2018. (15/24595-9, 13/07600-3, 14/21129-4, 13/50228-8)

DA CUNHA, FERNANDA F. M.; MUGNOL, KATIA C. U.; DE MELO, FILIPE M.; NASCIMENTO, MARTA V. S. Q.; DE AZEVEDO, RICARDO A.; SANTOS, RAQUEL T. S.; MAGALHAES, JESSICA A.; MIGUEL, DANILO C.; TADA, DAYANE B.; MORTARA, RENATO A.; et al. Peptide R18H from BRN2 Transcription Factor POU Domain Displays Antitumor Activity In Vitro and In Vivo and Induces Apoptosis in B16F10-Nex2 Cells. ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, v. 19, n. 3, p. 389-401, 2019. (15/05980-9, 14/21129-4)