Role of chromatin modifiers in the transcription dynamics of virulence factors of the human malaria parasite Plasmodium falciparum

• Grant number: 17/24267-7
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2018
• End date: March 31, 2021
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Gerhard Wunderlich
• Grantee: Gerhard Wunderlich
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Paulo Eduardo Martins Ribolla ; Wesley Luzetti Fotoran

Abstract

Malaria parasites strictly control gene expression in each phase of their complex life cycle, depending on the host environment. The control of expression is mostly at the transcriptional level, although post-translational mechanisms are also encountered (e.g. P-bodies). Transcriptional control is exerted by dynamic chromatin modification and the deliberate inhibition of chromatin modifiers may seriously interfere with or kill parasites. In this project, we focus on the role and importance of chromatin modifiers on variant gene transcription in blood stage Plasmodium falciparum parasites, which cause the most dangerous form of human malaria. These parasites are also still endemic in the Brazilian Amazon. In a previous study, we have created transgenic parasite lines which permit functional characterization (via ribozymes) of chromatin modifiers. Introducing also a hemagglutinine tag, we generated mutants in chromatin modifier genes of histone deactylases (SIR2A), histone demthylases (Jumonji-like demethylase 1, 2 and lysine histone demethylase 1, LSD-1). We also modified a DNA Cytosine methyltransferase, a acetyl histone transferase (SET2) and an AcetylCoA synthetase, which probably delivers acetyl rests for Acetyl histone transferases. We also modified three putative transcription factors of the ApiAP2 family which may be involved in variant gene transcription. Variant (var) genes encode adhesins which then may lead to severe malaria outcomes. We propose to elucidate by ChIPseq the chromosomal sites/genes in which the modified factors associate. Via the hemagglutinine tag, we will analyze which proteins coprecipitate with the modified proteins, using mass spec. Further, we propose to analyze coprecipitating (nc)RNAs which may play a decisive role in orchestrating the variegated transcription in the case of variant gene family transcription. The expected results will contribute to the understanding of the coordinating network that underlies gene transcription in blood stage malaria parasites, possibly revealing novel attack points for drugs. (AU)

Scientific publications

(8)

(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)

PRATA, ISADORA OLIVEIRA; GALINDO CUBILLOS, ELIANA FERNANDA; KRUGER, ARNE; BARBOSA, DEIBS; MARTINS, JOAQUIM; SETUBAL, JOAO CARLOS; WUNDERLICH, GERHARD. Plasmodium falciparum Acetyl-CoA Synthetase Is Essential for Parasite Intraerythrocytic Development and Chromatin Modification. ACS INFECTIOUS DISEASES, v. 7, n. 12, p. 3224-3240, DEC 10 2021. (17/24267-7, 16/12659-5, 18/08820-0, 15/26722-8)

DOMBROWSKI, JAMILLE GREGORIO; BARATEIRO, ANDRE; MACHADO PEIXOTO, ERIKA PAULA; CLAUDIO DA SILVA BARROS, ANDRE BOLER; DE SOUZA, RODRIGO MEDEIROS; CLARK, TAANE GREGORY; CAMPINO, SUSANA; WRENGER, CARSTEN; WUNDERLICH, GERHARD; PALMISANO, GIUSEPPE; et al. Adverse pregnancy outcomes are associated with Plasmodium vivax malaria in a prospective cohort of women from the Brazilian Amazon. PLoS Neglected Tropical Diseases, v. 15, n. 4, APR 2021. (17/03966-4, 17/03939-7, 18/18257-1, 19/12068-5, 15/26722-8, 17/24267-7, 20/06747-4, 18/20468-0, 20/04923-0, 18/15549-1, 17/05782-8)

CUBILLOS, ELIANA F. G.; PRATA, ISADORA OLIVEIRA; FOTORAN, WESLEY LUZETTI; RANFORD-CARTWRIGHT, LISA; WUNDERLICH, GERHARD. The Transcription Factor PfAP2-O Influences Virulence Gene Transcription and Sexual Development in Plasmodium falciparum. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, JUN 28 2021. (16/12659-5, 17/24267-7, 15/17174-7, 16/19145-7)

FOTORAN, WESLEY LUZETTI; KLEIBER, NICOLE; GLITZ, CHRISTIANE; WUNDERLICH, GERHARD. A DNA Vaccine Encoding Plasmodium falciparum PfRH5 in Cationic Liposomes for Dermal Tattooing Immunization. VACCINES, v. 8, n. 4, DEC 2020. (15/17174-7, 17/24267-7)

FOTORAN, WESLEY L.; DA SILVA, JAMILE RAMOS; GLITZ, CHRISTIANE; FERREIRA, LUIS CARLOS DE SOUZA; WUNDERLICH, GERHARD. Establishment of an Antiplasmodial Vaccine Based on PfRH5-Encoding RNA Replicons Stabilized by Cationic Liposomes. PHARMACEUTICS, v. 15, n. 4, p. 17-pg., 2023-04-01. (17/24267-7, 21/13727-2, 16/20045-7, 16/19145-7)

MACEDO-SILVA, TATIANE; DESAI, SANJAY A.; WUNDERLICH, GERHARD. Improved Plasmodium falciparum dilution cloning through efficient quantification of parasite numbers and c-SNARF detection. Malaria Journal, v. 20, n. 1, JUN 23 2021. (17/24267-7)

FOTORAN, WESLEY L.; MUENTEFERING, THOMAS; KLEIBER, NICOLE; MIRANDA, BEATRIZ N. M.; LIEBAU, EVA; IRVINE, DARRELL J.; WUNDERLICH, GERHARD. A multilamellar nanoliposome stabilized by interlayer hydrogen bonds increases antimalarial drug efficacy. Nanomedicine-Nanotechnology Biology and Medicine, v. 22, NOV 2019. (16/19145-7, 17/24267-7, 17/08626-7, 15/17174-7)

WUNDERLICH, GERHARD; BETZEL, CHRISTIAN; WRENGER, CARSTEN. Editorial: From Apicomplexan Genes to Drug Discovery. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, p. 2-pg., 2021-11-10. (15/26722-8, 19/00899-0, 17/24267-7)