Erasing the epigenetic memory and beginning to switch--the onset of antigenic switching of var genes in Plasmodium falciparum
Public Library of Science
Copyright: © 2012 Fastman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
This work was supported by a grant from the German Israeli Foundation [997/2008]. RD is supported by the Marie Curie International Reintegration Grant (IRG) , the United States-Israel Binational Science Foundation , and the Israeli Academy for Science [660/09]. RD is also supported by the Jacob and Lena Joels Memorial Foundation Senior Lectureship for Excellence in the Life and Medical Sciences. RN is supported by a BBSRC studentship. MR is funded by a Royal Society University Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Vol. 7 (3), article e34168
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