Studies on the mechanism of transcriptional control and switching of virulence-associated genes in Plasmodium falciparum

• Grant number: 12/23306-5
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2013
• End date: August 31, 2015
• 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 the malaria-causing protozoan Plasmodium studied so far possess gene families in their genome, some of which encode variant antigens associated to virulence and localize to the infected red blood cell surface. In Plasmodium falciparum, the most important gene families are the var genes which encode the cytoadherence-mediating PfEMP1 antigens, the rif genes encoding RIFIN antigens, Pfmc-2TM genes, and surf genes encoding the merozoite and infected red blood cell exposed SURFINs. Other Plasmodium species possess the pir superfamily, and these encode the VIR proteins (Plasmodium vivax), BIR (Plasmodium berghei), and CIR, YIR and KIR antigens, found in P. chabaudi, P. yoelii, and P. knowlesi, respectively. Except for var, the biological purpose of these gene families is unknown. While many reports focused on the transciption mode and expression of var genes, the control mechanisms for the other gene families remain largely unexplored. Apparently, var and rif gene loci are modified by the same epigenetic modifications which indicate if a determined locus is transcriptionally active or not. In the same way, chromatin modifying enzymes and also factors which associate to the silenced state are partially known. However, many question remain unanswered, such as: Despite the absence of a functional RNAi pathway, is there an influence of ncRNAs which perhaps interact with the variant gene locus to be transcribed after the next blood cell reinvasion? The stringent crosstalk which exists for var genes happens at which grade in other gene families such as rif, bir or even surf? Herein we propose to answer these questions using transfection of parasites with artificial variant gene loci in plasmids or artificial chromosomes carrying variant gene promoters controlling the resistence against antibiotics. We then monitor the variant gene transcription by either real time qPCR or by RNAseq employing the recently acquired SOLiD platform. We plan to monitor variant gene transcription not only in the human parasite (P. falciparum), but also in the murine model P. berghei. The expected results will shed a light on the transcription mode of the different variant gene families. In parallel, we are going to test the function of the recently described ApiAP2 transciption factors in this process and if they are responsible for the transcriptional control of var, rif and surf genes. (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)

FOTORAN, WESLEY L.; COLHONE, MARCELLE C.; CIANCAGLINI, PIETRO; STABELI, RODRIGO G.; WUNDERLICH, GERHARD. Merozoite-Protein Loaded Liposomes Protect against Challenge in Two Murine Models of Plasmodium Infection. ACS BIOMATERIALS SCIENCE & ENGINEERING, v. 2, n. 12, p. 2276-2286, DEC 2016. (12/23306-5, 15/17174-7, 12/18617-1)

DUQUE ARAUJO, ROSANA BEATRIZ; SILVA, TATIANE MACEDO; KAISER, CHARLOTTE SOPHIE; LEITE, GABRIELA FERNANDES; ALONSO, DIEGO; MARTINS RIBOLLA, PAULO EDUARDO; WUNDERLICH, GERHARD. Independent regulation of Plasmodium falciparum rif gene promoters. SCIENTIFIC REPORTS, v. 8, JUN 19 2018. (15/17174-7, 12/23306-5)

CABRAL, FERNANDA J.; VIANNA, LUCIANA G.; MEDEIROS, MARCIA M.; CARLOS, BIANCA CECHETTO; MARTHA, ROSIMEIRE D.; SILVA, NADIA MARIA; DA SILVA, LUIZ HILDEBRANDO P.; STABELI, RODRIGO G.; WUNDERLICH, GERHARD. Immunoproteomics of Plasmodium falciparum-infected red blood cell membrane fractions. Memórias do Instituto Oswaldo Cruz, v. 112, n. 12, p. 850-856, DEC 2017. (12/23306-5)

BILSLAND, ELIZABETH; VAN VLIET, LIISA; WILLIAMS, KEVIN; FELTHAM, JACK; CARRASCO, MARTA P.; FOTORAN, WESLEY L.; CUBILLOS, ELIANA F. G.; WUNDERLICH, GERHARD; GROTLI, MORTEN; HOLLFELDER, FLORIAN; et al. Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarial action of triclosan. SCIENTIFIC REPORTS, v. 8, JAN 18 2018. (15/03553-6, 15/19103-0, 12/23306-5)

CABRAL, FERNANDA J.; VIANNA, LUCIANA G.; MEDEIROS, MARCIA M.; CARLOS, BIANCA CECHETTO; MARTHA, ROSIMEIRE D.; SILVA, NADIA MARIA; DA SILVA, LUIZ HILDEBRANDO P.; STABELI, RODRIGO G.; WUNDERLICH, GERHARD. Immunoproteomics of Plasmodium falciparum-infected red blood cell membrane fractions. Memórias do Instituto Oswaldo Cruz, v. 112, n. 12, p. 7-pg., 2017-12-01. (12/23306-5)