title: Functional analysis of sirtuin genes in multiple Plasmodium falciparum strains.
abstract: Plasmodium falciparum, the causative agent of severe human malaria, employs antigenic variation to avoid host immunity. Antigenic variation is achieved by transcriptional switching amongst polymorphic var genes, enforced by epigenetic modification of chromatin. The histone-modifying 'sirtuin' enzymes PfSir2a and PfSir2b have been implicated in this process. Disparate patterns of var expression have been reported in patient isolates as well as in cultured strains. We examined var expression in three commonly used laboratory strains (3D7, NF54 and FCR-3) in parallel. NF54 parasites express significantly lower levels of var genes compared to 3D7, despite the fact that 3D7 was originally a clone of the NF54 strain. To investigate whether this was linked to the expression of sirtuins, genetic disruption of both sirtuins was attempted in all three strains. No dramatic changes in var gene expression occurred in NF54 or FCR-3 following PfSir2b disruption, contrasting with previous observations in 3D7. In 3D7, complementation of the PfSir2a genetic disruption resulted in a significant decrease in previously-elevated var gene expression levels, but with the continued expression of multiple var genes. Finally, rearranged chromosomes were observed in the 3D7 PfSir2a knockout line. Our results focus on the potential for parasite genetic background to contribute to sirtuin function in regulating virulence gene expression and suggest a potential role for sirtuins in maintaining genome integrity.
authors.affiliation: Department of Immunology & Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Merrick
authors.affiliation: Department of Immunology & Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Rays H Y
authors.initials: RH
authors.lastname: Jiang
authors.affiliation: Department of Immunology & Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Skillman
authors.affiliation: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Upeka
authors.initials: U
authors.lastname: Samarakoon
authors.affiliation: Department of Immunology & Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Moore
authors.affiliation: Department of Microbiology & Molecular Genetics, The Kuvin Center for the Study of Infectious and Tropical Diseases, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Dzikowski
authors.affiliation: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ferdig
authors.affiliation: Department of Immunology & Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Manoj T
authors.initials: MT
authors.lastname: Duraisingh
mesh_terms: D000940:Antigenic Variation; D055028:Comparative Genomic Hybridization; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006657:Histones / Q000378:metabolism; D010963:Plasmodium falciparum / Q000235:genetics* / Q000472:pathogenicity; D037761:Sirtuins / Q000235:genetics / Q000502:physiology*; D059505:Telomere Homeostasis; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology
chemical_list: D006657:Histones; D037521:Virulence Factors; D037761:Sirtuins