Regulation of P. falciparum egress from the host cell: identification of new targets

• Grant number: 15/19316-3
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: August 01, 2016
• End date: July 31, 2021
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Mauro Ferreira de Azevedo
• Grantee: Mauro Ferreira de Azevedo
• Host Institution: Instituto de Saúde e Sociedade (ISS). Universidade Federal de São Paulo (UNIFESP). Campus Baixada Santista. Santos , SP, Brazil
• Associated researchers: Gerhard Wunderlich ; Marcos Leoni Gazarini Dutra ; María Belén Cassera ; Paul R. Gilson
• Associated research grant(s): 18/12589-2 - Multi-user equipment approved in grant 15/19316-3: flow cytometer, AP.EMU
• Associated scholarship(s): 18/08989-5 - Evaluation of the combination of conditional gene expression in P. falciparum for the study of functional genome and potential antimalarials screening, BP.MS; 18/01742-4 - Mode of action of potential antimalarials, BP.TT; 17/15511-1 - Investigation of membrane permeabilization during Plasmodium falciparum egress, BP.MS; 17/05622-0 - Conditional gene expression in P. falciparum, BP.IC; 16/15298-3 - P. falciparum egress from the host cell: identification of new targets, BP.JP

Abstract

Despite successful efforts for its control, malaria is still a major public health problem in Brazil and in the World. The genome sequencing of several Plasmodium species as well as high through put transcriptomic and proteomic studies have allowed a better understanding about the parasite biology and its interaction with the host. In addition, thousands of compounds that inhibit parasite development and/or proliferation during in vitro cell culture have been identified, although the targets of most of them remain unknown. In a significantly lower scale, reverse genetics has allowed determining which genes encode for essential proteins for certain parasite stages and eventually to elucidate their function. Transgenic parasite lines have also been applied in the identification of compounds with anti-parasite effect and eventually in getting clues about their targets. Since post-graduation, I have worked with reverse genetics, investigating aspects of parasite biology, trying to improve the systems for conditional gene expression, and lately developing methods to investigate the targets of potential new antimalarial compounds. In this project, new conditions for conditional gene expression will be evaluated in order to provide lower leakage and thus better regulation of the genes of interest. Parasite transgenic lines that are conditional knockout for protein kinases G or calcium-dependent protein kinase 5, which also express the super bright reporter Nano-Luciferase in the parasitophorous vacuole or in the red blood cell cytosol, will be applied to investigate the role of these kinases in regulating egress and to identify other molecules required for the process. The targets of potential new anti-malarial compounds will be investigated regarding their inhibitory effect on aspects of parasite biology such as protein secretion and export, invasion and egress from the host cell and the function of the new permeation pathway. (AU)

Scientific publications

(6)

(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)

MACEDO-SILVA, TATIANE; DUQUE ARAUJO, ROSANA BEATRIZ; MEISSNER, KAMILA ANNA; FOTORAN, WESLEY LUZETTI; MEDEIROS, MARCIA MELO; DE AZEVEDO, MAURO FERREIRA; WUNDERLICH, GERHARD. Knockdown of the Plasmodium falciparum SURFIN4.1 antigen leads to an increase of its cognate transcript. PLoS One, v. 12, n. 8, AUG 11 2017. (15/17174-7, 12/23306-5, 13/12439-7, 15/19316-3)

MELO, POLLYANA M. S.; MALUF, SARAH EL CHAMY; AZEVEDO, MAURO F.; PASCHOALIN, THAYSA; BUDU, ALEXANDRE; BAGNARESI, PIERO; HENRIQUE-SILVA, FLAVIO; SOARES-COSTA, ANDREA; GAZARINI, MARCOS L.; CARMONA, ADRIANA K.. Inhibition of Plasmodium falciparum cysteine proteases by the sugarcane cystatin CaneCPI-4. Parasitology International, v. 67, n. 2, p. 233-236, APR 2018. (15/06861-3, 15/19316-3, 16/15298-3, 11/14403-4, 13/12913-0, 09/53840-0)

GOMES SMAUL, MAYRIM MACHADO; BUDU, ALEXANDRE; MONTAGNA, GEORGINA NURI; DA SILVA FERRARA, TAISE FERNANDA; MALUF, SARAH EL CHAMY; BAGNARESI, PIERO; FERREIRA MACHADO, MARCELO MARCONDES; DOS SANTOS, FELLIPE BRONZE; DE AZEVEDO, MAURO FERREIRA; CARMONA, ADRIANA KARAOGLANOVIC; et al. Plasmodium falciparum histidine triad protein and calmodulin modulates calcium homeostasis and intracellular proteolysis. Biochemical and Biophysical Research Communications, v. 503, n. 2, p. 722-728, SEP 5 2018. (12/24278-5, 16/15298-3, 14/07138-0, 16/02412-2, 15/19316-3, 13/12913-0, 15/00689-4, 15/11861-2, 15/07182-2, 11/20941-9)

VERDAGUER, I. B.; CRISPIM, M.; ZAFRA, C. A.; SUSSMANN, R. A. C.; BURITICA, N. L.; MELO, H. R.; AZEVEDO, M. F.; ALMEIDA, F. G.; KIMURA, E. A.; KATZIN, A. M.. Exploring Ubiquinone Biosynthesis Inhibition as a Strategy for Improving Atovaquone Efficacy in Malaria. Antimicrobial Agents and Chemotherapy, v. 65, n. 4, APR 2021. (18/12589-2, 17/22452-1, 15/19316-3)

PORTA, EXEQUIEL O. J.; VERDAGUER, IGNASI BOFILL; PEREZ, CONSUELO; BANCHIO, CLAUDIA; FERREIRA DE AZEVEDO, MAURO; KATZIN, ALEJANDRO M.; LABADIE, GUILLERMO R.. Repositioning Salirasib as a new antimalarial agent. MedChemComm, v. 10, n. 9, p. 1599-1605, SEP 1 2019. (17/22452-1, 15/19316-3)

GABRIEL, HELOISA B.; AZEVEDO, MAURO F.; KIMURA, EMILIA A.; KATZIN, ALEJANDRO M.. Plasmodium falciparum parasites overexpressing farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase are more resistant to risedronate. Memórias do Instituto Oswaldo Cruz, v. 113, n. 10, 2018. (17/22452-1, 14/23417-7, 15/12054-3, 15/19316-3, 16/15298-3)

Filed patent(s) as a result of this research project