Genomics and post-genomics approaches to study the human malarial parasites Plasmodium vivax and Plasmodium falciparum in the Brazilian Amazon

Abstract

In spite of intense research, malaria remains the most devastating parasitic disease of mankind with ca. 200-300 annual million cases and 1.7-2.4 million deaths mostly in children below five years of age. In the particular case of Brazil, the Amazon region is responsible for almost all the clinical malaria attacks, which last year accounted for more than 600,000 cases with a socio-economical burden of aroundl00-200 million dollars. Remarkably, the two most prevalent malarial species, Plasmodium falciparum and P. vivax are sympatric in the Brazilian Amazon, offering a unique opportunity for comparative studies. In 1997 an International Consortium between The Sanger Centre, TIGR and Stanford University launched the Genome Project of P. falciparum. In this same year, the construction of a representative library of P. vivax was reported, initiating strictu sensu the genomic era of human malaria research. Significantly, the completion of the P. falciparum genome as well as major advances on the genome of P. vivax, were recently announced at the Eleventh Meeting of the Malaria Genome Consortium (Hinxton, June 5th_6th). We thus propose to use genomic and post-genomic approaches to accelerate the discovery of three main research areas in P. falciparum and P. vivax that we have been investigating through alternative methodologies for the last 10 years: virulence, population genetics and chemotherapy. Moreover, through the interaction with the Center for Bioinformatics at USP, we propose to create a malaria data bank of sequences and micro-array images (MaIDB) to fully exploit all this new biological information. Virulence: Sequencing of the subtelomeric regions of P. falciparum and P. vivax has revealed the existence of multi-gene families encoding virulent determinants. We propose to determine the genomic repertoire of these multigene families in the Brazilian Amazon through the sequencing of -10 Mbp obtained from parasites of infected patients in different regions. With this information, microarrays representing the "Brazilian" repertoire of virulent genes from P. vivax and P. falciparum will be constructed and used to determine the pattern of expression of malaria patients with different clinical spectra, including samples from Asia and Africa. These results should reveal expression patterns associated with symptomatic vs. non-symptomatic patients as well as patterns associated with falciparum infections compromising the lungs and kidneys, the most prevalent pathology associated with malaria in the Brazilian Amazon. Moreover, the analysis of expressed sequences can reveal common motifs that could represent the basis of future and rational approaches to develop new vaccines and/or drugs against malaria... (AU)