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The humoral response against Plasmodium falciparum infected erythrocytes: parameters of protection in natural infections in the Amazon

Grant number: 09/17114-3
Support type:Regular Research Grants
Duration: February 01, 2010 - July 31, 2012
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Gerhard Wunderlich
Grantee:Gerhard Wunderlich
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The infection with the protozoans Plasmodium vivax and P. falciparum still is a major health problem in the Brazilian Amazon. Around 500,000 (malaria) cases are reported annually and 25% of these are caused by P. falciparum. An important virulence factor of P. falciparum - and eventually of P. vivax - is the infected red blood cells capacity to adhere to endothelial cell receptors or other uninfected erythrocytes, which ultimately leads to the severe formas of malaria, including death. In the case of P. falciparum, the cytoadhesive properties are mediated by members of the protein family PfEMP1, which are encoded by the mostly subtelomeric var genes. Due to ectopic recombination of telomers during meiosis, there are many different variants of PfEMP1. Together with the particular transcription mode of var genes (allelic exclusion), PfEMP1 thus allows a constant immune escape and the formation of new variants against which antibodies that inhibit or revert cytoadherence, are no longer functional. In a recent study, we reported that - in contrast to holoendemic areas such as Subsaharian Africa - the number of PfEMP1 variants seems limited in the Amazon, which puts the area in a especial situation. There are many infected individuals which are non-symptomatic carriers, apparently protected from severe disease or even acute malaria. In order to evaluate if antibodies against structures of the infected red blood cell (IRBC) are responsible for protection, we propose to measure first the existence of antibodies against the surface of IRBC in plasmas from symptomatic or non-symptomatic ("protected") individuals by flow cytometry. In parallel, we are going to measure the reversion or inhibition of IRBC cytoadherence by plasmas from either symptoamic or non-symptomatic individuals. The adherence-inhibitory properties are elucidated using 3 important receptor/ligand interactions, namely against CD36, ICAM-1 and CSA binding using a robust cell-based system which can even be used in flow conditions. We then propose to elucidate the identity of proteins which are differentially recognized by symptomatic or non-symptomatic plasma using high resolution mass spectrometry (Maldi-TOF-TOF). The expected results will shed a light on the role and quality of anti-PfEMP1 and anti-IRBC immunoglobulins in natural infections in the Amazon. As controls, we propose to use two transfected parasite lines which are either deficient in PfEMP1 and other variant proteins or deficient in any IRBC surface exposed antigen. This proposal is intended to support a network of three labs (UNIR/IPEPATRO, UNICAMP and ICB-USP) which each possess excellency in different techniques leading to disease-relevant research with field samples. (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)
CARLOS, BIANCA C.; FOTORAN, WESLEY L.; MENEZES, MARIA J.; CABRAL, FERNANDA J.; BASTOS, MARCELE F.; COSTA, FABIO T. M.; SOUSA-NETO, JAYME A.; RIBOLLA, PAULO E. M.; WUNDERLICH, GERHARD; FERREIRA, MARCELO U. Expressed var gene repertoire and variant surface antigen diversity in a shrinking Plasmodium falciparum population. Experimental Parasitology, v. 170, p. 90-99, NOV 2016. Web of Science Citations: 2.
BASSI FRATUS, ALESSANDRA SAMPAIO; CABRAL, FERNANDA JANKU; FOTORAN, WESLEY LUZETTI; MEDEIROS, MARCIA MELO; CARLOS, BIANCA CECHETTO; DALLA MARTHA, ROSIMEIRE; PEREIRA DA SILVA, LUIZ HILDEBRANDO; PINTO LOPES, STEFANIE COSTA; MARANHAO COSTA, FABIO TRINDADE; WUNDERLICH, GERHARD. Antibody recognition of Plasmodium falciparum infected red blood cells by symptomatic and asymptomatic individuals in the Brazilian Amazon. Memórias do Instituto Oswaldo Cruz, v. 109, n. 5, p. 598-607, AUG 2014. Web of Science Citations: 3.

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