Abstract
BackgroundThe evolutionary mechanisms structuring the expression pattern of variant surface antigen (VSA) families that allow pathogens to evade immune responses and establish chronic and repeated infections pose major challenges to theoretical research. In Plasmodium falciparum, the best-studied VSA family is erythrocyte membrane protein 1 (PfEMP1). Each parasite genome encodes about 60 PfEMP1 variants, which are important virulence factors and major targets of host antibody responses. Transcriptional switching is the basis of clonal PfEMP1 variation and immune evasion. A relatively conserved subset of PfEMP1 variants tends to dominate in non-immune patients and in patients with severe malaria, while more diverse subsets relate to uncomplicated infection and higher levels of pre-existing protective immunity.Methodology/Principal FindingsHere, we use the available molecular and serological evidence regarding VSAs, in particular PfEMP1, to formulate a mathematical model of the evolutionary mechanisms shaping VSA organization and expression patterns. The model integrates the transmission dynamics between hosts and the competitive interactions within hosts, based on the hypothesis that the VSAs can be organized into so-called dominance blocks, which characterize their competitive potential. The model reproduces immunological trends observed in field data, and predicts an evolutionary stable balance between inter-clonally conserved dominance blocks that are highly competitive within-host and diverse blocks that are favoured by immune selection at the population level.Conclusions/SignificanceThe application of a monotonic dominance profile to VSAs encoded by a gene family generates two opposing selective forces and, consequently, two distinct clusters of genes emerge in adaptation to naïve and partially immune hosts, respectively.
Highlights
People living in malaria endemic regions typically carry Plasmodium falciparum parasites throughout life, clinical symptoms decrease markedly with age [1]
Model outline On the basis of available experimental evidence summarized above, we hypothesize that the global repertoire pool of variants within a given variant surface antigen (VSA) family can be ordered into a dominance hierarchy that determines the order in which they are expressed in an infection
It has been suggested that this epidemiological pattern is due to the importance of VSA-specific immunity for clinical protection, to the non-random order in which immunity to specific VSAs is acquired, and to the association between particular VSAs with specific disease syndromes [5,44]
Summary
People living in malaria endemic regions typically carry Plasmodium falciparum parasites throughout life, clinical symptoms decrease markedly with age [1]. Antibodies undoubtedly form a critical component of immunity to the asexual blood stages [3], and the parasite-encoded variant surface antigens (VSAs) exported to the surface of infected erythrocytes (IEs) are important targets [4,5]. P. falciparum parasites possess several VSA families, of which the best characterized is P. falciparum erythrocyte membrane protein 1 (PfEMP1) encoded by approximately 60 var genes per genome [6]. The importance of PfEMP1 in malaria pathogenesis has motivated the development of theoretical models of diversity and immune selection [9,10,11]. In Plasmodium falciparum, the best-studied VSA family is erythrocyte membrane protein 1 (PfEMP1). Each parasite genome encodes about 60 PfEMP1 variants, which are important virulence factors and major targets of host antibody responses. A relatively conserved subset of PfEMP1 variants tends to dominate in non-immune patients and in patients with severe malaria, while more diverse subsets relate to uncomplicated infection and higher levels of pre-existing protective immunity
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