Multi-scale immune selection and the maintenance of structured antigenic diversity in the malaria parasite Plasmodium falciparum

Abstract

The most virulent malaria parasite, Plasmodium falciparum, makes use of extensive antigenic diversity to maximise its transmission potential. Parasite genomes contain several highly polymorphic gene families, whose products are the target of protective immune responses. The best studied of these are the PfEMP1 surface proteins, which are encoded by the var multi-gene family and are important virulence factors. During infection, the parasite switches expression between PfEMP1 variants in order to evade adaptive immune responses and prolong infection. On the population level, parasites appear to be structured with respect to their var genes into non-overlapping repertoires, which can lead to high reinfection rates. This non-random structuring of antigenic diversity can also be found at the level of individual var gene repertoires and var genes themselves. However, not much is known about the evolutionary determinants which select for and maintain this structure at different ecological scales. In this thesis I investigate the mechanisms by which multi-scale immune selection and other ecological factors influence the evolution of structured diversity. Using a suite of theoretical frameworks I show that treating diversity as a dynamic property, which emerges from the underlying infection and transmission processes, has a major effect on the relationship between the parasite’s transmis- sion potential and disease prevalence, with important implications for monitoring control efforts. Furthermore, I show that an evolutionary trade-off between within-host and between-host fitness together with functional constraints on diversification can explain the structured diversity found at both the repertoire and parasite population level and might also account for empirically observed exposure-dependent acquisition of immunity. Together, this work highlights the need to consider evolutionary factors acting at different ecological scales to gain a more comprehensive understanding of the complex immune-epidemiology of P. falciparum malaria.