Abstract
Antigenic variation in Plasmodium falciparum is regulated by transcriptional switches among members of the var gene family, each expressed in a mutually exclusive manner and encoding a different variant of the surface antigens collectively named PfEMP1. Antigenic switching starts when the first merozoites egress from the liver and begin their asexual proliferation within red blood cells. By erasing the epigenetic memory we created parasites with no var background, similar to merozoites that egress from the liver where no var gene is expressed. Creating a null-var background enabled us to investigate the onset of antigenic switches at the early phase of infection. At the onset of switching, var transcription pattern is heterogeneous with numerous genes transcribed at low levels including upsA vars, a subtype that was implicated in severe malaria, which are rarely activated in growing cultures. Analysis of subsequent in vitro switches shows that the probability of a gene to turn on or off is not associated with its chromosomal position or promoter type per se but on intrinsic properties of each gene. We concluded that var switching is determined by gene specific associated switch rates rather than general promoter type or locus associated switch rates. In addition, we show that fine tuned reduction in var transcription increases their switch rate, indicating that transcriptional perturbation can alter antigenic switching.
Highlights
Plasmodium falciparum causes the deadliest form of human malaria and its virulence is attributed in part to the ability of the parasites to undergo antigenic variation of immunodominant cell surface proteins to avoid immune recognition [1,2,3]
The major antigenic ligands responsible for cytoadhesion are members of the highly polymorphic PfEMP1 [4] proteins expressed on the surface of infected red blood cells
This fact argues that dynamics in transcription patterns of each population reflects switch rates rather than fitness cost of particular PfEMP1 expression
Summary
Plasmodium falciparum causes the deadliest form of human malaria and its virulence is attributed in part to the ability of the parasites to undergo antigenic variation of immunodominant cell surface proteins to avoid immune recognition [1,2,3].The major antigenic ligands responsible for cytoadhesion are members of the highly polymorphic PfEMP1 [4] proteins expressed on the surface of infected red blood cells (iRBC). Var genes have been classified into several subgroups based on the sequence similarity of their 59 UTRs [10,11] with subtelomeric var genes having either upsA or upsB promoters, whereas centrally located var genes have upsC promoters; var2csa, the var gene that was implicated in pregnancy associated malaria, has a unique upsE promoter. The proportions of these groups seem to be highly conserved between different parasite isolates [12,13]
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