A Plasmodium falciparum Histone Deacetylase regulates antigenic variation and gametocyte conversion

Bradley I. Coleman, Kristen M. Skillman, Rays H.Y. Jiang, Lauren M. Childs, Lindsey M. Altenhofen, Markus Ganter, Yvette Leung, Ilana Goldowitz, Björn F.C. Kafsack, Matthias Marti, Manuel Llinas, Caroline O. Buckee, Manoj T. Duraisingh

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)177-186
Number of pages10
JournalCell Host and Microbe
Volume16
Issue number2
DOIs
StatePublished - Aug 13 2014

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Antigenic Variation
Histone Deacetylases
Plasmodium falciparum
Histone Deacetylase 2
Virulence
Parasites
Gene Expression
Sex Differentiation
Sexual Development
Falciparum Malaria
Essential Genes
Genes
Immunity
Transcription Factors
Erythrocytes
Population

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Virology

Cite this

Coleman, B. I., Skillman, K. M., Jiang, R. H. Y., Childs, L. M., Altenhofen, L. M., Ganter, M., ... Duraisingh, M. T. (2014). A Plasmodium falciparum Histone Deacetylase regulates antigenic variation and gametocyte conversion. Cell Host and Microbe, 16(2), 177-186. https://doi.org/10.1016/j.chom.2014.06.014
Coleman, Bradley I. ; Skillman, Kristen M. ; Jiang, Rays H.Y. ; Childs, Lauren M. ; Altenhofen, Lindsey M. ; Ganter, Markus ; Leung, Yvette ; Goldowitz, Ilana ; Kafsack, Björn F.C. ; Marti, Matthias ; Llinas, Manuel ; Buckee, Caroline O. ; Duraisingh, Manoj T. / A Plasmodium falciparum Histone Deacetylase regulates antigenic variation and gametocyte conversion. In: Cell Host and Microbe. 2014 ; Vol. 16, No. 2. pp. 177-186.
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Coleman, BI, Skillman, KM, Jiang, RHY, Childs, LM, Altenhofen, LM, Ganter, M, Leung, Y, Goldowitz, I, Kafsack, BFC, Marti, M, Llinas, M, Buckee, CO & Duraisingh, MT 2014, 'A Plasmodium falciparum Histone Deacetylase regulates antigenic variation and gametocyte conversion', Cell Host and Microbe, vol. 16, no. 2, pp. 177-186. https://doi.org/10.1016/j.chom.2014.06.014

A Plasmodium falciparum Histone Deacetylase regulates antigenic variation and gametocyte conversion. / Coleman, Bradley I.; Skillman, Kristen M.; Jiang, Rays H.Y.; Childs, Lauren M.; Altenhofen, Lindsey M.; Ganter, Markus; Leung, Yvette; Goldowitz, Ilana; Kafsack, Björn F.C.; Marti, Matthias; Llinas, Manuel; Buckee, Caroline O.; Duraisingh, Manoj T.

In: Cell Host and Microbe, Vol. 16, No. 2, 13.08.2014, p. 177-186.

Research output: Contribution to journalArticle

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T1 - A Plasmodium falciparum Histone Deacetylase regulates antigenic variation and gametocyte conversion

AU - Coleman, Bradley I.

AU - Skillman, Kristen M.

AU - Jiang, Rays H.Y.

AU - Childs, Lauren M.

AU - Altenhofen, Lindsey M.

AU - Ganter, Markus

AU - Leung, Yvette

AU - Goldowitz, Ilana

AU - Kafsack, Björn F.C.

AU - Marti, Matthias

AU - Llinas, Manuel

AU - Buckee, Caroline O.

AU - Duraisingh, Manoj T.

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N2 - Summary 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.

AB - Summary 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.

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Coleman BI, Skillman KM, Jiang RHY, Childs LM, Altenhofen LM, Ganter M et al. A Plasmodium falciparum Histone Deacetylase regulates antigenic variation and gametocyte conversion. Cell Host and Microbe. 2014 Aug 13;16(2):177-186. https://doi.org/10.1016/j.chom.2014.06.014