TY - JOUR
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 - Llinás, Manuel
AU - Buckee, Caroline O.
AU - Duraisingh, Manoj T.
N1 - Funding Information:
We thank Katy Shaw Saliba and Deepali Ravel for aid with this work. Support for this research was provided by a National Science Foundation Graduate Research Fellowship (B.I.C.), NIH T32 5T32HL007574-31 (K.M.S), American Heart Association 13POST16850007 (K.M.S), HHMI fellowship of the Damon Runyon Cancer Research Foundation (B.F.C.K.), NIH/NIAID R21 AI105328 (M.M.), NIH R01 AI076276 with support from the Centre for Quantitative Biology (P50GM071508) (M.L.), Award U54GM088558 from the National Institute of General Medical Sciences (L.M.C., C.O.B.), and a Burroughs Wellcome Fund New Investigator in the Pathogenesis of Infectious Diseases Fellowship (M.T.D.).
PY - 2014/8/13
Y1 - 2014/8/13
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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U2 - 10.1016/j.chom.2014.06.014
DO - 10.1016/j.chom.2014.06.014
M3 - Article
C2 - 25121747
AN - SCOPUS:84908159405
SN - 1931-3128
VL - 16
SP - 177
EP - 186
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 2
ER -