A network for an integrative biology in neglected diseases: bridging epigenetics, metabolism and cell cycle in pathogenic trypanosomatids

• Grant number: 18/14432-3
• Support Opportunities: Research Projects - Thematic Grants
• Start date: April 01, 2019
• End date: March 31, 2023
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Agreement: MRC, UKRI ; Newton Fund, with FAPESP as a partner institution in Brazil
• Principal Investigator: Ariel Mariano Silber
• Grantee: Ariel Mariano Silber
• Principal researcher abroad: Michael Barrett
• Institution abroad: University of Glasgow, Scotland
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais:( Últimos ): Julia Pinheiro Chagas da Cunha ; Luiz Ricardo Orsini Tosi
• Pesquisadores principais:( Antigos ): Maria Carolina Quartim Barbosa Elias Sabbaga
• Associated researchers: Julia Pinheiro Chagas da Cunha ; Luiz Ricardo Orsini Tosi ; Maria Carolina Quartim Barbosa Elias Sabbaga ; Otavio Henrique Thiemann ; Renata Rosito Tonelli
• Associated research grant(s): 21/14074-2 - Establishing expression systems for the biophysical analysis of integral membrane proteins of pathogenic kinetoplastids, AV.EXT; 21/01070-9 - Mitochondrial redox shuttles as novel mechanisms to regulate energy homeostasis in Trypanosoma cruzi parasites, AV.BR
• Associated scholarship(s): 22/12315-5 - Biochemical and functional characterization of the asparagine synthetases of Trypanosoma cruzi, BP.DD; 22/04890-0 - Characterization of the mitochondrial pathway of thiolation of tRNAs in Trypanosoma cruzi, BP.MS; 21/12469-0 - Genome-wide approaches to reveal epigenomic structure in trypanosomes subjected to metabolic states changes and during cell cycle, BP.PD; + associated scholarships 19/25769-1 - Defining the epigenetic landscape in Trypanosoma Cruzi and Leishmania major cells subjected to DNA injury, BP.PD; 19/21354-1 - Chasing for chromatine-associated proteins and histone PTMs patterns associated to cell stages and metabolic states in trypanosomes, BP.PD; 19/19690-3 - Genome-wide approaches to reveal epigenomic structure in trypanosomes subjected to metabolic states changes and during cell cycle, BP.PD; 17/10256-3 - Relevance of L-asparagine and its catabolism in the cell biology and bioenergetics of Trypanosoma cruzi, BP.PD - associated scholarships

Abstract

Pathogenic trypanosomatids such as Leishmania spp. and Trypanosoma cruzi are the causative agents of leishmaniosis and Chagas disease, a group of neglected diseases endemic in the tropical and subtropical belt of the planet and the Americas, respectively. The therapeutic approaches against these diseases are largely unsatisfactory due to toxicity and emergence of resistance. Thus, new drugs are urgently needed against these threats. In the last 20 years, a profusion of OMICS approaches resulted in a deeper comprehension of cellular processes allowing the survival of these parasites in their hosts, a sine qua non condition for establishing the infection and triggering the pathology. However, most of these studies approached cellular processes individually; as a consequence our comprehension of their integration is poor. The goal of this proposal is to understand the interaction among three essential core processes: metabolism, cell cycle and epigenetic gene expression regulation, with the goal of establishing a broader comprehension of how the metabolic environment affects parasite proliferation and determines inheritable adaptations. The information to be obtained will be fundamental to elucidate the basic biology of these pathogens as well as to discover new druggable points, greatly contributing for the development of novel therapies. (AU)

Scientific publications

(13)

(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)

LIMA, ALEX R. J.; DE ARAUJO, CHRISTIANE B.; BISPO, SALOE; PATANE, JOSE; SILBER, ARIEL M.; ELIAS, M. CAROLINA; DA CUNHA, JULIA P. C.. Nucleosome landscape reflects phenotypic differences in Trypanosoma cruzi life forms. PLOS PATHOGENS, v. 17, n. 1, JAN 2021. (18/15553-9, 19/19690-3, 18/14432-3, 16/50050-2, 13/07467-1)

NASCIMENTO, JANAINA F.; SOUZA, RODOLPHO O. O.; ALENCAR, MAYKE B.; MARSICCOBETRE, SABRINA; MURILLO, ANA M.; DAMASCENO, FLAVIA S.; GIRARD, RICHARD B. M. M.; MARCHESE, LETICIA; LUEVANO-MARTINEZ, LUIS A.; ACHJIAN, RENAN W.; et al. How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosomabrucei cell. PLOS PATHOGENS, v. 19, n. 7, p. 35-pg., 2023-07-01. (21/12938-0, 18/14432-3)

JERONIMO LIMA, ALEX RANIERI; DE SOUSA SILVA, HERBERT GUIMARAES; POUBEL, SALOE; ROSON, JULIANA NUNES; OLIVEIRA DE LIMA, LOYZE PAOLA; COSTA-SILVA, HELLIDA MARINA; GONCALVES, CAMILA SILVA; GALANTE, PEDRO A. F.; HOLETZ, FABIOLA; MOTTA, MARIA CRISTINA MACHADO M.; et al. Open chromatin analysis in Trypanosoma cruzi life forms highlights critical differences in genomic compartments and developmental regulation at tDNA loci. EPIGENETICS & CHROMATIN, v. 15, n. 1, p. 16-pg., 2022-06-01. (13/07467-1, 18/15553-9, 20/02708-4, 18/14432-3, 19/19834-5, 19/19690-3)

DOS SANTOS, DENIS AMILTON; SOUZA, HIGO FERNANDO SANTOS; SILBER, ARIEL M.; CAMPOS BRASIL DE SOUZA, TATIANA DE ARRUDA; AVILA, ANDREA RODRIGUES. Protein kinases on carbon metabolism: potential targets for alternative chemotherapies against toxoplasmosis. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 13, p. 14-pg., 2023-05-23. (21/12938-0, 18/14432-3)

PAVANI, RAPHAEL S.; DE LIMA, LOYZE P.; LIMA, ANDRE A.; FERNANDES, CARLOS A. H.; FRAGOSO, STENIO P.; CALDERANO, SIMONE G.; ELIAS, MARIA CAROLINA. Nuclear export of replication protein A in the nonreplicative infective forms of Trypanosoma cruzi. FEBS Letters, v. 594, n. 10, p. 1596-1607, MAY 2020. (16/50050-2, 14/02978-0, 18/14432-3, 18/21785-0, 13/07467-1)

SHIRATSUBAKI, ISABEL S.; FANG, XIN; SOUZA, RODOLPHO O. O.; PALSSON, BERNHARD O.; SILBER, ARIEL M.; SIQUEIRA-NETO, JAIR L.. Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi. PLoS Neglected Tropical Diseases, v. 14, n. 10, OCT 2020. (16/06034-2, 18/14432-3)

MANTILLA, BRIAN S.; PAES-VIEIRA, LISVANE; DIAS, FELIPE DE ALMEIDA; CALDERANO, SIMONE G.; ELIAS, MARIA CAROLINA; COSENTINO-GOMES, DANIELA; OLIVEIRA, PEDRO L.; MEYER-FERNANDES, JOSE ROBERTO; SILBER, ARIEL M.. Higher expression of proline dehydrogenase altered mitochondrial function and increased Trypanosoma cruzi differentiation in vitro and in the insect vector. Biochemical Journal, v. 478, n. 21, p. 3891-3903, NOV 2021. (16/06034-2, 18/14432-3)

MICHELS, PAUL A. M.; VILLAFRAZ, ORIANA; PINEDA, ERIKA; ALENCAR, MAYKE B.; CACERES, ANA J.; SILBER, ARIEL M.; BRINGAUD, FREDERIC. Carbohydrate metabolism in trypanosomatids: New insights revealing novel complexity, diversity and species-unique features. Experimental Parasitology, v. 224, MAY 2021. (18/14432-3, 16/06034-2)

SILVA, MARCELO S. DA; VITARELLI, MARCELA O.; VIALA, VINCENT LOUIS; TSANTARLIS, KATHERINE; PIRES, DAVID DA SILVA; FRANCO, THIAGO A.; DE AZEVEDO, INACIO L. M. J.; ELIAS, MARIA CAROLINA; TONELLI, RENATA R.. Clues on the dynamics of DNA replication in Giardia lamblia. Journal of Cell Science, v. 136, n. 10, p. 13-pg., 2023-05-01. (17/07693-2, 20/10277-3, 18/14432-3, 13/07467-1, 14/24170-5, 19/02918-1, 20/00694-6, 16/50050-2, 19/10753-2)

SOUZA, RODOLPHO ORNITZ OLIVEIRA; DAMASCENO, FLAVIA SILVA; MARSICCOBETRE, SABRINA; BIRAN, MARC; MURATA, GILSON; CURI, RUI; BRINGAUD, FREDERIC; SILBER, ARIEL MARIANO. Fatty acid oxidation participates in resistance to nutrient-depleted environments in the insect stages of Trypanosoma cruzi. PLOS PATHOGENS, v. 17, n. 4, APR 2021. (18/14432-3, 16/06034-2)

DE LIMA, LOYZE P.; POUBEL, SALOE BISPO; YUAN, ZUO-FEI; ROSON, JULIANA NUNES; DE LUNA VITORINO, FRANCISCA NATHALIA; HOLETZ, FABIOLA BARBIERI; GARCIA, BENJAMIN A.; CHAGAS DA CUNHA, JULIA PINHEIRO. Improvements on the quantitative analysis of Trypanosoma cruzi histone post translational modifications: Study of changes in epigenetic marks through the parasite's metacyclogenesis and life cycle. JOURNAL OF PROTEOMICS, v. 225, APR 15 2020. (18/21785-0, 17/06104-3, 18/14432-3, 18/15553-9, 13/07467-1, 17/18344-9)

VILLAFRAZ, ORIANA; BIRAN, MARC; PINEDA, ERIKA; PLAZOLLES, NICOLAS; CAHOREAU, EDERN; ORNITZ OLIVEIRA SOUZA, RODOLPHO; THONNUS, MAGALI; ALLMANN, STEFAN; TETAUD, EMMANUEL; RIVIERE, LOIC; et al. Procyclic trypanosomes recycle glucose catabolites and TCA cycle intermediates to stimulate growth in the presence of physiological amounts of proline. PLOS PATHOGENS, v. 17, n. 3, MAR 2021. (18/14432-3, 16/06034-2)

MENEZES, ANA PAULA; MURILLO, ANA MILENA; DE CASTRO, CAMILA GACHET; BELLINI, NATALIA KARLA; TOSI, LUIZ RICARDO ORSINI; THIEMANN, OTAVIO HENRIQUE; ELIAS, MARIA CAROLINA; SILBER, ARIEL MARIANO; DA CUNHA, JULIA PINHEIRO CHAGAS. Navigating the boundaries between metabolism and epigenetics in trypanosomes. Trends in Parasitology, v. 39, n. 8, p. 14-pg., 2023-08-01. (21/12469-0, 18/14432-3, 18/15553-9, 21/03219-0, 19/21354-1, 20/00694-6)