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

TitleThe effect of Plasmodium falciparum Sir2a histone deacetylase on clonal and longitudinal variation in expression of the var family of virulence genes.
Publication TypeJournal Article
Year of Publication2010
AuthorsMerrick CJ, Dzikowski R, Imamura H, Chuang J, Deitsch K, Duraisingh MT
JournalInt J Parasitol
Volume40
Issue1
Pagination35-43
Date Published2010 Jan
ISSN1879-0135
KeywordsAnimals, Antigenic Variation, Cells, Cultured, Erythrocytes, Flow Cytometry, Gene Expression Regulation, Gene Silencing, Group III Histone Deacetylases, Histone Deacetylases, Humans, Malaria, Falciparum, Plasmodium falciparum, Reverse Transcriptase Polymerase Chain Reaction, Virulence
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 (DeltaSir2a) parasites were generated. var gene expression was then measured qualitatively, quantitatively and longitudinally over extended periods in culture. DeltaSir2a 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 upsEvar gene subclasses. The total var transcript level was two to three-fold higher in DeltaSir2a 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.

DOI10.1016/j.ijpara.2009.06.012
Alternate JournalInt J Parasitol
PubMed ID19666023

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