Malaria research: A perspective from Brazil

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1 FAPESP Week 2011 Malaria research: A perspective from Brazil Marcelo Urbano Ferreira University of São Paulo, Brazil muferrei@usp.br

2 Malaria distribution worldwide

3 If more than 90% of all malaria infections worldwide occur in Africa why should we care about malaria in Brazil?

4 Malaria differs across the world according to parasite species transmission intensity patterns of drug resistance levels of antigenic diversity acquired immunity clinical features of disease

5 Malaria in Brazil 350,000 clinical cases/year (99% of them in Amazonia) Less than 100 malaria-related deaths/year Plasmodium vivax predominates (>85% of all cases) Clinical disease in all age groups

6 Malaria research in Brazil: from field to laboratory

7 Amazonian International Center of Excellence in Malaria Research (ICEMR) University of California, San Diego, USA Cayetano Heredia University, Peru University of São Paulo, Brazil State University of São Paulo, Brazil Wadsworth Center, New York, USA NIH-supported ( ), US$1.2 Mi/year

8 Hypothesis to be addressed by the Amazonian ICEMR: Asymptomatic parasite carriage and environmental changes are major contributors to malaria transmission across Amazonia

9 Brazil s study site: Remansinho

10 Brazil s study site: Remansinho Remansinho maps to a deforestation hotspot detected by INPE in 2011

11 Antigenic diversity in malaria parasites Origins, evolution, and consequences for acquired immunity

12 Genetic diversity in malaria parasites: an apparent paradox Little sequence diversity is found in Plasmodium falciparum housekeeping genes and non-coding DNA segments

13 Genetic diversity in malaria parasites: an apparent paradox Little sequence diversity is found in Plasmodium falciparum housekeeping genes and non-coding DNA segments, but most surface antigens are highly polymorphic.

14 Explaining the apparent paradox: Surface antigens evolve much faster that other sequences, due to increased recombination rates followed by positive selection.

15 Explaining the apparent paradox: Surface antigens evolve much faster that other sequences or the highly divergent alleles of antigencoding genes are very old and may predate the split between Plasmodium falciparum and its sister species, P. reichenowi.

16 Testing hypotheses: Merozoite surface proteins MSP-1, MSP-2 and MSP-6 of P. falciparum

17 Merozoite surface proteins are vaccine-candidate antigens

18 Merozoite surface proteins (MSP-1, MSP-2 and MSP-6) They display allelic dimorphism: all variants may be grouped into two major allelic classes. The origins and evolution of allelic dimorphism remain little studied.

19 Research questions: How recombination generates new alleles in malaria antigens? How allelic dimorphism has originated?

20 Repetitive domains in MSP-1 and MSP- 2 are prone to strand-slippage recombination

21 An example of strand-slippage recombination: the circumsporozoite protein of Plasmodium falciparum NVDP NANP

22 Evolution of MSP-1 repeats

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24 Allelic dimorphism: the one-fourth rule T LCA T LCA Under neutral evolution, the average sequence divergence within major branches is one fourth of the sequence divergence between branches. =T LCA /4 T LCA =T LCA /4 <T LCA /4 Neutral evolution Balancing selection Dimorphism

25 Allelic dimorphism: the one-fourth rule T LCA T LCA In allelic dimorphism, there is extensive divergence between allelic classes but little variation within each allelic class =T LCA /4 T LCA =T LCA /4 <T LCA /4 Neutral evolution Balancing selection Dimorphism

26 Can a single population bottleneck explain allelic dimorphism? bottleneck

27 Ancient dimorphism in MSP-1: looking at the distinguished relative, Plasmodium reichenowi Polley et al. MBP 2005

28 P. reichenowi P. falciparum K1 MAD20? K1 MAD20 Speciation (4-6 million years ago) K1 MAD20 Common ancestral (~27 million years)

29 P. reichenowi P. falciparum K1 MAD20? K1 MAD20 Ancient, trans-specific polymorphism? Speciation (4-6 million years ago) K1 MAD20 Common ancestral (~27 million years)

30 Recent dimorphism in MSP-2 (after speciation) P. reichenowi MSP-2 de Plasmodium reichenowi IC1 FC27 GGSA 5-12X ESNSPSPPITTT (repetição R1) (repetição R2) P. falciparum

31 Mixed origins of MSP-6 dimorphism 7 Roy et al. Gene 2009

32 Different time frames in the origin of allelic dimorphism in malaria antigens Divergence time Old Recent

33 A single population bottleneck CAN NOT explain allelic dimorphism in MSPs bottleneck

34 Thank you! (07/51/99-0) (470570/2006-7) (RO 1 A )