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Individual variation in malaria risk: causes and consequences in Amazonian populations

Abstract

Extensive research has examined why some people have repeated Plasmodium falciparum malaria attacks in Sub-Saharan Africa while others remain free of disease most of the time. In contrast, malaria risk heterogeneity remains little studied in regions where P. vivax is the dominant species. Are repeatedly infected people in vivax malaria settings such as the Amazon just unlucky? Here we aim to explore specific factors - including human and vector genetic polymorphism, acquired antibody-mediated immunity, and variation in parasite virulence - that can modulate the individual risk of P. vivax infection and disease in well characterized malaria-endemic Amazonian communities. We combine classical epidemiological approaches, molecular genotyping of humans, vectors and parasites, and functional antibody assays with quantitative genetics, mathematical modeling and vector biology to explore longitudinally collected data and samples from a unique population-based cohort study carried out in the main malaria transmission hotspot of Brazil. We aim to: (a) estimate the contribution of human genetics, not limited to known or suspected "malaria resistance genes", to individual malaria risk variation in Brazil; (b) to compare the differential impact of a specific human genetic polymorphism, pyruvate kinase deficiency, on P. falciparum and P. vivax malaria risk; (c) to investigate the association between naturally acquired antibodies to a key asexual blood-stage of P. vivax antigen and malaria risk; (d) to test the hypothesis that less virulent P. vivax lineages are positively selected as malaria vectors become less abundant and transmission declines; (e) to estimate the population-wide impact of specific malaria control interventions targeted at high-risk individuals; and (f) to determine how the biological heterogeneity of vectors affects the transmission dynamics of malaria considering its population structure and its preference for certain individuals (e.g., infected people). We argue that individual risk variation must be considered when designing and implementing strategies for malaria control and elimination. (AU)

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