Virulence gene dynamics in the human malaria parasite

人类疟疾寄生虫的毒力基因动态

• 批准号: MR/K000535/1
• 负责人: Catherine Merrick
• 金额: $ 18.08万
• 依托单位: Keele University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK000535%2F1
• 关键词: Virulence; gene; dynamics; human; malaria

The proposed research concerns the most important human malaria parasite, Plasmodium falciparum. Malaria is one of the world's most debilitating infectious diseases, killing almost a million people every year and affecting up to 300 million. Most of the deaths occur in young children in sub-Saharan Africa, but adults can also suffer from malaria throughout their lives, reducing quality of life and retarding economic development in endemic countries. The lack of an effective vaccine and the emergence of drug-resistant parasites mean that there is now an urgent need for research leading to a better understanding of the malaria parasite, and hence to new vaccine targets and treatment strategies for this disease. The malaria parasite causes illness via the infection of red blood cells. It multiplies inside these cells and modifies their surfaces with proteins called PfEMP1s that bind to the walls of blood vessels. This is crucial for parasite survival as it removes infected cells from the circulating blood and protects them from passing through the spleen, which might recognize and destroy them. It also contributes to disease, with severe malaria being particularly associated with the accumulation of infected cells in vessels of the brain and placenta. It is therefore of great interest to malaria biologists to understand the mechanisms that control the expression of these adhesive PfEMP1 proteins.PfEMP1s are not expressed uniformly by all malaria parasites: instead, individual parasites regularly switch between different variants. This allows them to stay ahead of the immune system and sustain a chronic infection for months or even years. The parasites have a large, variable family of 'var' genes for different PfEMP1 proteins and they vary the expression of these genes by so-called 'epigenetic switching'. Furthermore, var genes recombine very readily to generate new variants, so each parasite strain - of which there are many hundreds circulating in endemic areas - has a unique repertoire of possible surface proteins. This is one reason why immunity to repeated malaria infections is slow to develop in humans: every new parasite strain looks different to the immune system, so people can be re-infected repeatedly throughout their lives. Understanding, and ultimately interfering with, the expression, switching and recombination of var genes - and thus the variant expression of PfEMP1 proteins - could be a key to more effective immune control of malaria. Therefore, this research focuses on a possible biological mechanism for switching between var genes and for generating new variants. An unusual DNA structure called a G-quadruplex that is concentrated around var genes may affect both of these processes. Experiments to investigate this idea will include stabilizing the G-quadruplexes with specific chemicals and testing the effect on var gene expression. G-quadruplexes will also be isolated to test their effect on 'reporter' genes (genes coding for an easily-measurable product, such as a fluorescent protein). Finally, we will also test the effects of mutating some proteins called helicases that unwind the G-quadruplex DNA structures. These studies will lead to a better understanding of the mechanisms underlying var gene dynamics, and may ultimately inform new strategies to combat malaria, since var genes - and the PfEMP1s that they encode - are central to malarial disease. The outcomes of the research will be published in open-access scientific journals and presented at international conferences. They will be communicated to the general public via summaries on appropriate websites and via science-writing in magazines and/or online. Work such as this remains vital as long as the malaria parasite continues to cause an immense burden of human disease.

这项拟议的研究涉及人类最重要的疟疾寄生虫--恶性疟原虫。疟疾是世界上最令人衰弱的传染病之一，每年导致近100万人死亡，影响多达3亿人。大多数死亡病例发生在撒哈拉以南非洲的幼儿身上，但成年人也可能终生患有疟疾，降低了流行国家的生活质量，阻碍了经济发展。缺乏有效的疫苗和出现抗药性寄生虫意味着，现在迫切需要进行研究，以便更好地了解疟疾寄生虫，从而为这种疾病制定新的疫苗目标和治疗策略。疟疾寄生虫通过感染红细胞而致病。它在这些细胞内繁殖，并用一种名为PfEMP1的蛋白质来修饰它们的表面，这种蛋白质与血管壁结合。这对寄生虫的生存至关重要，因为它将感染细胞从循环血液中移除，并保护它们不会通过脾，后者可能会识别和摧毁它们。它还会导致疾病，尤其是严重疟疾与脑血管和胎盘中感染细胞的聚集有关。因此，疟疾生物学家对了解控制这些粘附性PfEMP1蛋白表达的机制非常感兴趣。PfEMP1并不是所有疟疾寄生虫都统一表达的：相反，个别寄生虫经常在不同的变种之间切换。这使他们能够领先于免疫系统，并将慢性感染持续数月甚至数年。寄生虫对不同的PfEMP1蛋白有一个庞大的、可变的“var”基因家族，它们通过所谓的“表观遗传转换”来改变这些基因的表达。此外，var基因很容易重组以产生新的变种，因此每一种寄生虫株--在流行地区有数百种--都有独特的可能的表面蛋白谱系。这就是为什么对反复疟疾感染的免疫力在人类身上发展缓慢的原因之一：每一种新的寄生虫株对免疫系统来说看起来都不同，所以人们可能会在一生中反复感染。了解并最终干预var基因的表达、切换和重组--从而导致PfEMP1蛋白的变异表达--可能是更有效地免疫控制疟疾的关键。因此，本研究着眼于var基因之间切换和产生新的变种的可能的生物学机制。一种被称为G-四联体的不寻常的DNA结构集中在var基因周围，可能会影响这两个过程。研究这一想法的实验将包括用特定的化学物质稳定G-四链，并测试其对var基因表达的影响。G-四联体也将被分离出来，以测试它们对报告基因(编码一种容易测量的产物，如荧光蛋白的基因)的影响。最后，我们还将测试突变一些名为解旋酶的蛋白质的效果，这些解旋酶可以解开G-四链DNA结构。这些研究将导致更好地理解var基因动力学的潜在机制，并最终可能为抗击疟疾的新战略提供信息，因为var基因及其编码的PfEMP1是疟疾的核心。研究成果将发表在开放获取的科学期刊上，并在国际会议上公布。它们将通过适当网站上的摘要以及杂志和/或在线上的科学写作向普通公众传播。只要疟疾寄生虫继续造成人类疾病的巨大负担，这样的工作就仍然至关重要。

项目成果

The in vivo RNA structurome of the malaria parasite Plasmodium falciparum, a protozoan with an A/U-rich transcriptome.

• DOI: 10.1371/journal.pone.0270863
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7

The in vivo RNA structurome of the malaria parasite Plasmodium falciparum , a protozoan with an A/T-rich transcriptome

疟原虫恶性疟原虫（一种富含 A/T 转录组的原生动物）的体内 RNA 结构组

• DOI: 10.1101/2021.04.29.441925
• 发表时间: 2021
• 作者: Dumetz F

G-quadruplex RNA motifs influence gene expression in the malaria parasite Plasmodium falciparum.

• DOI: 10.1093/nar/gkab1095
• 发表时间: 2021-12-02
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Dumetz F;Chow EY;Harris LM;Liew SW;Jensen A;Umar MI;Chung B;Chan TF;Merrick CJ;Kwok CK
• 通讯作者: Kwok CK

RecQ helicases in the malaria parasite Plasmodium falciparum affect genome stability, gene expression patterns and DNA replication dynamics.

• DOI: 10.1371/journal.pgen.1007490
• 发表时间: 2018-07
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Claessens A;Harris LM;Stanojcic S;Chappell L;Stanton A;Kuk N;Veneziano-Broccia P;Sterkers Y;Rayner JC;Merrick CJ
• 通讯作者: Merrick CJ

G-quadruplexes in pathogens: a common route to virulence control?

病原体中的 G-四链体：毒力控制的常见途径？

• DOI: 10.17863/cam.37840
• 发表时间: 2015
• 作者: Harris L