title: A Plasmodium falciparum histone deacetylase regulates antigenic variation and gametocyte conversion.
abstract: The asexual forms of the malaria parasite Plasmodium falciparum are adapted for chronic persistence in human red blood cells, continuously evading host immunity using epigenetically regulated antigenic variation of virulence-associated genes. Parasite survival on a population level also requires differentiation into sexual forms, an obligatory step for further human transmission. We reveal that the essential nuclear gene, P. falciparum histone deacetylase 2 (PfHda2), is a global silencer of virulence gene expression and controls the frequency of switching from the asexual cycle to sexual development. PfHda2 depletion leads to dysregulated expression of both virulence-associated var genes and PfAP2-g, a transcription factor controlling sexual conversion, and is accompanied by increases in gametocytogenesis. Mathematical modeling further indicates that PfHda2 has likely evolved to optimize the parasite's infectious period by achieving low frequencies of virulence gene expression switching and sexual conversion. This common regulation of cellular transcriptional programs mechanistically links parasite transmissibility and virulence.
authors.affiliation: Department of Immunology & Infectious Diseases Harvard School of Public Health, Boston, MA 02115 USA.
authors.forename: Bradley I
authors.initials: BI
authors.lastname: Coleman
authors.affiliation: Department of Immunology & Infectious Diseases Harvard School of Public Health, Boston, MA 02115 USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Skillman
authors.affiliation: Department of Immunology & Infectious Diseases Harvard School of Public Health, Boston, MA 02115 USA.
authors.forename: Rays H Y
authors.initials: RHY
authors.lastname: Jiang
authors.affiliation: Department of Epidemiology and Center for Communicable Disease Dynamics, Harvard School of Public Health, Boston MA 02115 USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Childs
authors.affiliation: Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton NJ 08544 USA.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Altenhofen
authors.affiliation: Department of Immunology & Infectious Diseases Harvard School of Public Health, Boston, MA 02115 USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Ganter
authors.affiliation: Department of Immunology & Infectious Diseases Harvard School of Public Health, Boston, MA 02115 USA.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Leung
authors.affiliation: Department of Immunology & Infectious Diseases Harvard School of Public Health, Boston, MA 02115 USA.
authors.forename: Ilana
authors.initials: I
authors.lastname: Goldowitz
authors.affiliation: Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton NJ 08544 USA.
authors.forename: Björn F C
authors.initials: BFC
authors.lastname: Kafsack
authors.affiliation: Department of Immunology & Infectious Diseases Harvard School of Public Health, Boston, MA 02115 USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Marti
authors.affiliation: Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton NJ 08544 USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Llinás
authors.affiliation: Department of Epidemiology and Center for Communicable Disease Dynamics, Harvard School of Public Health, Boston MA 02115 USA.
authors.forename: Caroline O
authors.initials: CO
authors.lastname: Buckee
authors.affiliation: Department of Immunology & Infectious Diseases Harvard School of Public Health, Boston, MA 02115 USA.
authors.forename: Manoj T
authors.initials: MT
authors.lastname: Duraisingh
mesh_terms: D000595:Amino Acid Sequence; D000953:Antigens, Protozoan / Q000276:immunology*; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D017125:Genes, Protozoan; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000502:physiology*; D006790:Host-Parasite Interactions; D006801:Humans; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000166:cytology / Q000201:enzymology*; D015800:Protozoan Proteins / Q000502:physiology*; D014774:Virulence / Q000235:genetics
chemical_list: D000953:Antigens, Protozoan; D006570:Heterochromatin; D015800:Protozoan Proteins; D006655:Histone Deacetylases