Towards understanding of expression control in Malaria parasites: from variant gene families in Plasmodium falciparum to pathogeny and inhibition of transmission

• Grant number: 21/13727-2
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2022
• End date: December 31, 2024
• 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

Abstract

All species of Plasmodium encode variant gene families in their genome, which possess different purposes and often relate to immune invasion or pathogenic processes. In recent years, data accumulated pointing to a complex network of regulation of variant gene families at a transcriptional and post-transcriptional level. We have invested in the function of specific putative plant-like transcription factors and chromatin modifiers to access their influence on variant gene expression. We could show that specific phylum-unique factors - AP2-O and AP2-EXP - participate in the enigmatic process of selective expression of determined members of variant gene families. Interestingly, these transcription factors are refractory to knockout, but do not interfere in vitro growth of Plasmodium falciparum under partial (~80%) knockdown. Nevertheless, higher levels of these factors are critical for later sexual stages, since partial knockdown abrogates effective development in the mosquito. In this project, we propose to pursue several goals: At the molecular level, we will elucidate the interactome of these two transcription factors of the ApiAP2 family using a novel proteomic approach. Additionally, the role of two histone demethylases (Jumonji-like demethylase 2, and Lysine histone demethylase - PfLSD1) and a DNA modifying methyl transferase (PfDNMT) on variant and global gene transcription are further explored. Further, we will approach the effect of temporary knockdown of the essential Exosome-RNAse PfRrp6 and the helicase PfRecQ01. In order to find roles of these enzymes also for transmission stages, we propose to perform mosquito infection experiments, which will be conducted with our collaborators at Glasgow University. Using the same vector/transfectant/knockdown approach as for the chromatin modifiers and AP2 factors, we will also invest in the chaperone-adaptor factors AHA2 and AHA4 from P. falciparum, contributing to the work of a group from São Carlos. (AU)

Scientific publications

(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)

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)

OLIVEIRA, DOUGLAS DAVISON DA SILVA; PAZ, FRANCIARLI; BRITO, NICOLAS PETERSON FERREIRA; KRUGER, ARNE; MARTINHO, ANA CLARA CASSIANO; LAPIERRE, THIBAULT JOSEPH WILLIAM JACQUES DIT; SOUZA, FELIPE DE OLIVEIRA; MALTAROLLO, VINICIUS G.; KRONENBERGER, THALES; MENDES, MARINA SENA; et al. Synthesis, design, and optimization of a potent and selective series of pyridylpiperazines as promising antimalarial agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 275, p. 16-pg., 2024-06-29. (18/08820-0, 21/13727-2, 15/26722-8, 17/24267-7, 17/03966-4)

ORTEGA SEPULVEDA, LUISA FERNANDA; DE OLIVEIRA, GABRIELA MENDES; NUNES CHAGAS, ELAINE HELLEN; WILD, NELE; DA PAZ, FRANCIARLI SILVA; WRENGER, CARSTEN; WUNDERLICH, GERHARD. Plasmodial Transcription Factors and Chromatin Modifiers as Drug Targets. FUTURE PHARMACOLOGY, v. 3, n. 4, p. 16-pg., 2023-12-01. (21/13727-2, 15/26722-8)