Decoding Plasmodium signaling at molecular level as a new tool to the development of new antimalarials

• Grant number: 17/08684-7
• Support Opportunities: Research Projects - Thematic Grants
• Start date: February 01, 2019
• End date: August 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: Célia Regina da Silva Garcia
• Grantee: Célia Regina da Silva Garcia
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Fabio Trindade Maranhão Costa ; Maria Regina D'Império Lima
• Associated research grant(s): 19/05708-8 - Calcium signaling in Plasmodium falciparum gametocytes, AV.EXT; 21/06607-0 - Multi-user equipment approved in grant 2017/08684-7: BRET, AP.EMU
• Associated scholarship(s): 24/22379-6 - Dissecting Antimalarial Efficacy of GlaxoSmithKline Compounds Across Parasite cycles and BRET studies into the GPCR-like Protein PvSR1, BP.DD; 24/06392-2 - Preparation and maintenance of material for studying Plasmodium falciparum by cytometry, BP.TT; 22/15522-1 - Signaling pathways and function of Plasmodium falciparum serpentine receptors SR1 and SR10, BP.PD; + associated scholarships 23/05364-2 - Preparation and maintenance of material for study on Plasmodium falciparum by cytometry, BP.TT; 22/10919-0 - Preparation and maintenance of material for study in Plasmodium falciparum by cytometrym as a tool to develop new antimalarials, BP.TT; 22/06132-5 - Construction of tagging and knockdown systems of the serpentine receptor 10 (SR10) in Plasmodium falciparum, BP.IC; 22/06187-4 - Construction of aptamer based knockdown of apetela2 nuclear protein (AP2) in Plasmodium falciparum, BP.IC; 22/02317-0 - Studies of GPCR-like PfSR12 signal transduction mechanisms in mammalian cells and in Plasmodium falciparum, BP.PD; 21/11213-1 - Decoding aspects of Plasmodium cell and molecular biology as a tool to develop new antimalarials, BP.TT; 20/08988-9 - Evaluation of compounds with antimalarial potential and study of the signal transduction mechanism of GPCR (G-Protein Coupled Receptor) like PfSR25 in Plasmodium falciparum, BP.DD; 19/27121-9 - Maintenance of Laboratory of Cell Biology and cell cultivation HEK293T., BP.TT; 19/08974-0 - Maintenance of Cell Biology Laboratory and culture of HEK293T cells, BP.TT; 19/09490-7 - Screening of novel ligands for PfSR1, a putative GPCR-like receptor and identification of potential IP3 receptor in calcium signaling in the Plasmodium falciparum, BP.PD - associated scholarships

Abstract

Malaria stands as the third most dangerous infectious disease after HIV/AIDS and tuberculosis that afflict mankind. The last decade studies pointed that pathogens have developed sophisticated cell signaling networks that allow for both cell-cell communication as well as sensing the external environment. In this direction, single cell protozoan parasites have to develop systems to withstand relatively large alterations in their external environments, including existing in the mammalian host with complex defense systems. In addition to depicting a complex biology, with a sexual and asexual developmental stages, malaria parasite, is exposed to distinct microenvironments within the vector cycle as well as during its development inside a vertebrate. The overall objective of this project is to understand how the parasite detects signaling from its milieu, what are the molecular components involved in transducing this signaling. We recently reported that purinergic signaling could be involved in TNF perception by P. falciparum. We plan to dissect the involvement of purinergic receptor signaling in P. falciparum cell cycle thus unraveling what is the participation of a P2X7 receptor in TNF signaling. We will use the PfGCaMP3 parasites as well as other molecular and cellular tools to understand signaling pathways in malaria parasite aiming to disrupt this signaling. (AU)

Scientific publications

(19)

(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)

SANTOS, BENEDITO M.; DIAS, BARBARA K. M.; NAKABASHI, MYNA; GARCIA, CELIA R. S.. The Knockout for G Protein-Coupled Receptor-Like PfSR25 Increases the Susceptibility of Malaria Parasites to the Antimalarials Lumefantrine and Piperaquine but Not to Medicine for Malaria Venture Compounds. FRONTIERS IN MICROBIOLOGY, v. 12, MAR 15 2021. (18/07177-7, 17/08684-7)

DIAS, BARBARA K. M.; NAKABASHI, MYNA; ALVES, MARINA RANGEL RODRIGUES; PORTELLA, DANIELLE PAGLIAMINUTO; DOS SANTOS, BENEDITO MATHEUS; ALMEIDA, FAHYME COSTA DA SILVA; RIBEIRO, RAMIRA YURI; SCHUCK, DESIREE C.; JORDAO, ALESSANDRO KAPPEL; GARCIA, CELIA R. S.. The Plasmodium falciparum eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle. Journal of Pineal Research, v. 69, n. 3, p. 17-pg., 2020-08-07. (18/07177-7, 17/08684-7)

DOS SANTOS, BENEDITO M.; PEREIRA, PEDRO H. S.; GARCIA, CELIA R. S.. Molecular basis of synchronous replication of malaria parasites in the blood stage. Current Opinion in Microbiology, v. 63, p. 210-215, OCT 2021. (17/08684-7, 20/08988-9)

ALVES, EDUARDO; NAKAYA, HELDER; GUIMARES, EUZEBIO; GARCIA, CELIA R. S.. Combining IP3 affinity chromatography and bioinformatics reveals a novel protein-IP3 binding site on Plasmodium falciparum MDR1 transporter*. CURRENT RESEARCH IN MICROBIAL SCIENCES, v. 4, p. 7-pg., 2022-12-19. (17/08684-7, 18/14933-2, 18/07177-7)

DOS SANTOS, BENEDITO M.; PECENIN, MATEUS F.; BORGES-PEREIRA, LUCAS; SPRINGER, ERIC; PRZYBORSKI, JUDE M.; MARTINS-JR, DAVID C.; HASHIMOTO, RONALDO F.; GARCIA, CELIA R. S.. The genetically encoded calcium indicator GCaMP3 reveals spontaneous calcium oscillations at asexual stages of the human malaria parasite Plasmodium falciparum. Molecular and Biochemical Parasitology, v. 260, p. 10-pg., 2024-08-24. (20/08988-9, 17/08684-7, 18/07177-7, 15/22308-2, 18/21934-5)

BORGES-PEREIRA, LUCAS; DIAS, BARBARA K. M.; SINGH, MANEESH KUMAR; GARCIA, CELIA R. S.. Malaria parasites and circadian rhythm: New insights into an old puzzle. CURRENT RESEARCH IN MICROBIAL SCIENCES, v. 2, p. 3-pg., 2021-12-01. (17/08684-7, 18/07177-7, 16/14411-0, 19/09490-7)

SINGH, MANEESH K.; TESSARIN-ALMEIDA, GIULLIANA; DIAS, BARBARA K. M.; PEREIRA, PEDRO SCARPELLLI; COSTA, FAHYME; PRZYBORSKI, JUDE M.; GARCIA, CELIA R. S.. A nuclear protein, PfMORC confers melatonin dependent synchrony of the human malaria parasite P. falciparum in the asexual stage. SCIENTIFIC REPORTS, v. 11, n. 1, JAN 21 2021. (17/08684-7, 19/09490-7, 11/51295-5, 18/07177-7)

PEREIRA, PEDRO H. S.; GARCIA, CELIA R. S.. Melatonin action in Plasmodium infection: Searching for molecules that modulate the asexual cycle as a strategy to impair the parasite cycle. Journal of Pineal Research, v. 70, n. 1, OCT 2020. (18/07177-7, 17/08684-7)

SINGH, MANEESH KUMAR; DE MENEZES DIAS, BARBARA KARINA; GARCIA, CELIA R. S.. Role of Melatonin in the Synchronization of Asexual Forms in the Parasite Plasmodium falciparum. BIOMOLECULES, v. 10, n. 9, SEP 2020. (17/08684-7, 19/09490-7)

PEREIRA, PEDRO H. S.; GARCIA, CELIA R. S.. Evidence of G-Protein-Coupled Receptors (GPCR) in the Parasitic Protozoa Plasmodium falciparum-Sensing the Host Environment and Coupling within Its Molecular Signaling Toolkit. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 22, NOV 2021. (17/08684-7, 18/07177-7)

MALLAUPOMA, LENNA ROSANIE CORDERO; DIAS, BARBARA KARINA DE MENEZES; SINGH, MANEESH KUMAR; HONORIO, RUTE ISABEL; NAKABASHI, MYNA; KISUKURI, CAMILA DE MENEZES; PAIXAO, MARCIO WEBER; GARCIA, CELIA R. S.. Decoding the Role of Melatonin Structure on Plasmodium falciparum Human Malaria Parasites Synchronization Using 2-Sulfenylindoles Derivatives. BIOMOLECULES, v. 12, n. 5, p. 15-pg., 2022-05-01. (18/12986-1, 17/08684-7, 19/09490-7)

DIAS, BARBARA K. M.; NAKABASHI, MYNA; ALVES, MARINA RANGEL RODRIGUES; PORTELLA, DANIELLE PAGLIAMINUTO; DOS SANTOS, BENEDITO MATHEUS; ALMEIDA, FAHYME COSTA DA SILVA; RIBEIRO, RAMIRA YURI; SCHUCK, DESIREE C.; JORDAO, ALESSANDRO KAPPEL; GARCIA, CELIA R. S.. ThePlasmodium falciparumeIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle. Journal of Pineal Research, v. 69, n. 3, AUG 2020. (17/08684-7, 18/07177-7)

DEDA, DAIANA K.; IGLESIAS, BERNARDO A.; ALVES, EDUARDO; ARAKI, KOITI; GARCIA, CELIA R. S.. Porphyrin Derivative Nanoformulations for Therapy and Antiparasitic Agents. Molecules, v. 25, n. 9, MAY 2020. (17/08684-7, 18/07177-7, 18/21489-1)

BORGES-PEREIRA, LUCAS; THOMAS, SAMANTHA J.; DOS ANJOS E SILVA, AMANDA LAIZY; BARTLETT, PAULA J.; THOMAS, ANDREW P.; GARCIA, CELIA R. S.. The genetic Ca2+ sensor GCaMP3 reveals multiple Ca2+ stores differentially coupled to Ca2+ entry in the human malaria parasite Plasmodium falciparum. Journal of Biological Chemistry, v. 295, n. 44, p. 14998-15012, OCT 30 2020. (18/07177-7, 16/14411-0, 17/08684-7)

SANTOS, BENEDITO M. DOS; GONZAGA, DANIEL T. G.; DA SILVA, FERNANDO C.; FERREIRA, VITOR F.; GARCIA, CELIA R. S.. Plasmodium falciparum Knockout for the GPCR-Like PfSR25 Receptor Displays Greater Susceptibility to 1,2,3-Triazole Compounds That Block Malaria Parasite Development. BIOMOLECULES, v. 10, n. 8, AUG 2020. (17/08684-7)

DOS SANTOS, BENEDITO MATHEUS; MALLAUPOMA, LENNA ROSANIE CORDERO; PECENIN, MATEUS FILA; MOHANTY, ABHINAB; LU, ANGELA; BARTLETT, PAULA J.; THOMAS, ANDREW P.; GAMO, FRANCISCO-JAVIER; GARCIA, CELIA R. S.. Unravelling the mode of action of the Tres Cantos Antimalarial Set (TCAMS): investigating the mechanism of potent antimalarial compounds potentially targeting the human serotonin receptor. Malaria Journal, v. 24, n. 1, p. 19-pg., 2025-02-14. (17/08684-7, 20/08988-9)

DIAS, BARBARA K. M.; MOHANTY, ABHINAB; GARCIA, CELIA R. S.. Melatonin as a Circadian Marker for Plasmodium Rhythms. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 25, n. 14, p. 13-pg., 2024-07-01. (22/15522-1, 18/07177-7, 17/08684-7)

SCARPELLI, PEDRO H.; PECENIN, MATEUS F.; GARCIA, CELIA R. S.. Intracellular Ca2+ Signaling in Protozoan Parasites: An Overview with a Focus on Mitochondria. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 1, JAN 2021. (17/08684-7, 18/07177-7)

DOS SANTOS, BENEDITO M.; PRZYBORSKI, JUDE M.; GARCIA, CELIA R. S.. Changes in K+ Concentration as a Signaling Mechanism in the Apicomplexa Parasites Plasmodium and Toxoplasma. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 8, p. 11-pg., 2023-04-01. (17/08684-7, 20/08988-9)