Epigenomics and gametocytogenesis in the rodent malaria model, Plasmodium berghei

Q Science (General);QR Microbiology

Power, Bridget Joanne ; Wellcome Trust (WELLCOTR) ; Waters, Andrew

University:University of Glasgow

Department:Institute of Infection Immunity and Inflammation

关键词: Malaria, Plasmodium, gametocytogenesis, transmission, gametocyte, Plasmodium berghei.;   

Others  :  http://theses.gla.ac.uk/71046/27/2018PowerPhD.pdf

来源: University of Glasgow

【 摘 要 】

In 2017, an estimated 219 million people became infected with a Plasmodium parasite, resulting in malaria. Of the 435,000 deaths, 61% were in children aged 5 years and under. With increasing incidences of resistance to standard anti-malarial therapies, and the unprecedented failure of rapid diagnostic tests in Sub-Saharan Africa, there is an onus on the scientific community to identify new mechanisms by which parasites of the Plasmodium genus can be detected and targeted for eradication. In the present study, the epigenetic mechanisms by which the rodent malaria parasite, Plasmodium berghei, regulates its transmission were examined. In malaria parasites, transmission from a mosquito vector to a mammalian host is mediated by a stage of sexual development known as gametocytogenesis. Using reverse genetics approaches, in combination with fluorescence-assisted cell sorting, a previously undetermined role for histone acetyltransferase 1 (HAT1) in Plasmodium intraerythrocytic growth and gametocytogenesis was determined. In a similar manner, histone deacetylase 1 (HDA1), a protein previously shown to be transcribed alongside proteins AP2-G and LSD2 prior to schizont egress, was determined to be essential to optimal asexual growth of P. berghei.In addition to these functional studies, acid extraction of histones and tandem mass spectrometry were used to determine the array of histone post-translational modifications that define the mature asexual schizont from sexual-stage gametocytes. To examine some of these sex-specific histone modifications further, a novel chromatin-immunoprecipitation/high-throughput sequencing technique, called ‘ChIPmentation’, was used to identify the genomic targets of four epigenetic modifications in mature asexual parasites, with a view to future comparison of these histone marks to those found at gametocyte stage. This study also represents the first time that H3K122 acetylation has been examined at any stage in any Plasmodium species.The insights gleaned from this study add to our current knowledge of the landscape of epigenetic modifications and their regulatory enzymes at asexual and sexual stages of Plasmodium parasite development.