The effect of Plasmodium falciparum Sir2a histone deacetylase on clonal and longitudinal variation in expression of the var family of virulence genes

Catherine J. Merrick, Ron Dzikowski, Hideo Imamura, Jeffrey Chuang, Kirk Deitsch, Manoj T. Duraisingh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Plasmodium falciparum, the most important causative agent of human malaria, undergoes antigenic variation as a means of prolonging infection and ensuring transmission between hosts. Clonal variation is observed in the surface adhesins expressed on infected erythrocytes: primarily in the PfEMP1 adhesin encoded by the large var gene family. The sirtuin PfSIR2A was the first protein discovered to have a major influence on antigenic variation in P. falciparum. In the absence of PfSIR2A, normal silencing of the variantly-expressed var gene family is partially deregulated. To thoroughly investigate the role of PfSIR2A in controlling antigenic variation, multiple independent clones of wildtype and PfSIR2A-knockout (ΔSir2a) parasites were generated. var gene expression was then measured qualitatively, quantitatively and longitudinally over extended periods in culture. ΔSir2a parasites were found to activate about 10 specific var genes in every independent clone analyzed. The activated genes were biased towards the upsA, upsBA and upsE var gene subclasses. The total var transcript level was two to three-fold higher in ΔSir2a parasites than in wildtype parasites and at least one transcript - encoding the pregnancy malaria adhesin VAR2CSA - was successfully translated and expressed on the infected cell surface. In the absence of PfSIR2A, antigenic switching over time was also diminished, although not abolished. This work expands our understanding of clonal antigenic variation in this important human pathogen and demonstrates a central role for PfSIR2A in regulating both the variant expression of specific var gene subsets and the overall quantity of var gene expression.

Original languageAmerican English
Pages (from-to)35-43
Number of pages9
JournalInternational Journal for Parasitology
Volume40
Issue number1
DOIs
StatePublished - Jan 2010

Keywords

  • Antigenic variation
  • Epigenetic
  • Plasmodium falciparum
  • Silencing
  • Sirtuin
  • var

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