恶性疟原虫表面抗原var基因家族相互排斥性表达表观遗传调控机制的研究

Plasmodium falciparum, the most deadly parasite of human malaria, has a variant surface antigen gene family consisting of multiple var genes that contribute to a major pathogenesis event in severe malaria. Through a clonal expression profile of var genes controlled by epigenetic regulations, P. falciparum could avoid the host antibody response and spleen-dependent parasite killing as an immune evasion mechanism. Recently, we demonstrated that a histone lysine methyltransferase PfSET2vs regulates silencing of the entire var gene family. In addition, we showed a previously unknown role of var-derived antisense long noncoding RNAs (lncRNAs) in transcription of var genes. However, the molecular mechanism of mutually exclusive expression of the var gene family still remains unknown nowadays. To further explore the epigenetic mechanism in controlling mutually exclusive expression of var genes, I plan to (1) identify transcription factors which associate with var anti-sense lncRNA in transcriptional regulation of var genes; 2) characterize novel lncRNAs and transcription regulators that control silencing of var genes in association with PfSET2vs; and 3) uncover key regulators and their functional roles in controlling mutually exclusive expression of the var gene family in a broad manner. This study will shed light on understanding how P. falciparum escapes human immune system via epigenetic mechanisms regulating mutually exclusive expression of var genes, and provide new targets in the development of malaria vaccines and antimalarials.

恶性疟原虫是最致命的人体疟疾寄生虫，其致病过程的一个关键组分是表面抗原var基因家族。通过表观遗传机制的调节，每个疟原虫同时只能表达一个var基因，从而帮助其逃避人体免疫反应。我们已发现组蛋白赖氨酸甲基化酶PfSET2vs是var基因转录沉默的关键因子；而且，var基因的负链lncRNA介导了其mRNA的转录激活。但目前，调节var基因相互排斥性表达的分子机制仍未阐明。为进一步探索var 基因相互排斥性表达的表观遗传调节机制，本项目拟开展如下研究：1）鉴定与var基因负链lncRNA共同调节var基因转录激活的转录因子；2）筛选与PfSET2vs协同抑制var基因转录的其他lncRNA及调节因子；3）揭示对var基因具有广谱调控作用的关键因子，及其作用的分子机制。本研究对于系统阐明var基因家族参与恶性疟原虫免疫逃逸的表观遗传调控机制具有重要意义，也将为疟疾疫苗及抗疟药的研发提供新的靶点。

疟疾是一种严重威胁人类健康和生命的寄生虫疾病，而恶性疟原虫是致命性最强的疟疾寄生虫。var基因家族所编码的PfEMP1蛋白，是疟原虫致病过程中的一个关键组分。通过表观遗传机制的调节，每个疟原虫在某个时刻只能表达一个var基因，从而帮助其逃避人体免疫反应。在国家自然科学基金的资助下，我们应用表观遗传学理论，揭示了var基因的负链lncRNAs、广谱性因子PfRecQ1等因子调控恶性疟原虫免疫逃逸的分子机制，相关研究已经发表在Parasites & Vectors 2017, Front Microbiol 2018, PNAS 2019a & 2019b等杂志上（两篇共同通讯作者，两篇共同作者）。此外，我们还从中找到了一个新的表观遗传因子DM，该DM蛋白影响了PfEMP1蛋白在受感染红细胞膜表面的呈递。目前我们正在对其中的机制进行深入研究。总之，本研究阐明了var基因家族参与恶性疟原虫免疫逃逸的表观遗传调控机制，并且为疟疾疫苗及抗疟药的研发提供了新靶点。

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