Erasing the Epigenetic Memory and Beginning to Switch—The Onset of Antigenic Switching of var Genes in Plasmodium falciparum

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.

Immune Characterization of Plasmodium falciparum Parasites with a Shared Genetic Signature in a Region of Decreasing Transmission

“…Still, while this result is unusual, it is not unprecedented, since other groups have reported the expression of UpsA var genes in uncomplicated malaria cases (47). Of note, UpsA var expression is usually lost with culture adaptation (52,53), so the upregulation of UpsA var genes is unlikely to be an artifact due to short-term culture adaptation. Additionally, we found a higher prevalence of 2-cysteine-containing PfEMP-1 molecules, which have been associated with UpsA var genes (47), in CGS parasites than in non-CGS parasites, potentially indicating a rosetting (47,51) or endothelial protein C receptor (EPCR)-binding (54) phenotype.…”

Spleen-Dependent Regulation of Antigenic Variation in Malaria Parasites: Plasmodium knowlesi SICAvar Expression Profiles in Splenic and Asplenic Hosts

“…The majority of studies on the mechanisms of P. falciparum var gene expression, carried out since the discovery of the var gene family in 1995 [36-38], have been based on in vitro work, reviewed in 39,64,65. While clearly challenging for P. falciparum studies, the importance of studying antigenic variation in the context of the host environment has been stressed [1,66] and an increasing number of studies over the last decade have aimed to compare, contrast, and model results generated from in vivo or ex vivo iRBC samples acquired from human P. falciparum infections [26,59,66-75].…”

The antigenic switching network of Plasmodium falciparum and its implications for the immuno-epidemiology of malaria

“…Several studies have noted that var genes located near the centres of chromosomes tend to be more highly transcribed in vitro than those in subtelomeric location (Frank et al, 2007; Peters et al, 2007; Enderes et al, 2011; Zhang et al, 2011; Fastman et al, 2012), and it has been suggested that this might be due to low deactivation rates (Frank et al, 2007). In this study, we found that high transcription levels are confined to a subset of central genes that encode only four PfEMP1 binding domains (termed Type 1 var genes [Gardner et al, 2002]) and, importantly, are the result of high activation biases rather than low off-rates.…”