Immune selection and within-host competition can structure the repertoire of variant surface antigens in Plasmodium falciparum -a mathematical model

TY - JOUR

T1 - Immune selection and within-host competition can structure the repertoire of variant surface antigens in Plasmodium falciparum -a mathematical model

AU - van Noort, Sander P

AU - Nunes, Marta C

AU - Weedall, Gareth D

AU - Hviid, Lars

AU - Gomes, M Gabriela M

PY - 2010

Y1 - 2010

N2 - Background: The 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 Findings: Here, 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/Significance: The 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.

AB - Background: The 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 Findings: Here, 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/Significance: The 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.

U2 - 10.1371/journal.pone.0009778

DO - 10.1371/journal.pone.0009778

M3 - Journal article

C2 - 20339540

SN - 1932-6203

VL - 5

SP - e9778

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 3

ER -