Toxoplasma: Sphingolipids in host-parasite interactions syntheses versus scavenging

弓形虫：宿主-寄生虫相互作用中的鞘脂合成与清除

• 批准号: BB/D52396X/1
• 负责人: Paul Denny
• 金额: $ 25.42万
• 依托单位: Durham University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD52396X%2F1
• 关键词: Toxoplasma; Sphingolipids; host; parasite; interactions

The apicomplexans are a large group of related, single-celled microscopic organisms that cause a range of diseases (including malaria) in both humans and economically important domestic animals. One of these, Toxoplasma gondii, can infect most species of warm-blooded animals causing a disease known as toxoplasmosis. In recent times Toxoplasma has come to prominence as causing serious diseases in patients whose defences (immune response) against such invading organisms have been damaged, such as those suffering from acquired immunodeficiency syndrome ¿ AIDS. In addition, infection of unborn lambs with Toxoplasma is a major cause of miscarriage, leading to annual multi-million pound losses to UK sheep farmers. Humans and other animals usually become infected with Toxoplasma following ingestion of contaminated food or faeces. Subsequently, the parasites can invade almost any of the cells that make up the body of an animal. However, in most cases this infection does not cause serious disease, instead Toxoplasma is controlled by the immune response of the animal and retreats into cysts in the brain or in muscle tissue. These cysts can remain throughout the animal¿s life without causing any problems. However, a damaged (in an AIDS patient) or undeveloped (in an unborn animal) immune response is unable to control the parasite in this way leading to disease. Within the animal cell Toxoplasma manufactures many substances it needs for growth, however, it is also able to scavenge various materials that it uses for its own purposes. This research proposal aims to investigate how the parasite manufactures or acquires an important component of its plasma membrane (a fatty barrier that separates the inside of the parasite cell from the external environment) ¿ sphingolipid. This will help us understand how Toxoplasma grows within animal cells and how it subsequently causes disease. In addition, the observation that some of the machinery needed to make sphingolipids in Toxoplasma (and in other apicomplexans) is very unusual may eventually allow the development of new drugs against these organisms.

顶复菌是一大类相关的单细胞微生物，可引起人类和经济上重要的家畜的一系列疾病（包括疟疾）。其中一种弓形虫可以感染大多数种类的温血动物，引起一种称为弓形虫病的疾病。近年来，弓形虫引起了人们的关注，它会导致对这种入侵生物体的防御（免疫反应）受到损害的患者产生严重疾病，例如患有获得性免疫缺陷综合症（艾滋病）的患者。此外，未出生的羔羊感染弓形虫是流产的主要原因，每年给英国养羊户造成数百万英镑的损失。人类和其他动物通常在摄入受污染的食物或粪便后感染弓形虫。随后，寄生虫可以侵入几乎所有构成动物身体的细胞。然而，在大多数情况下，这种感染不会引起严重的疾病，相反，弓形虫受到动物免疫反应的控制，并退回到大脑或肌肉组织中的囊肿中。这些囊肿可以在动物的一生中保留而不会造成任何问题。然而，受损的（艾滋病患者）或未发育的（未出生的动物）免疫反应无法以这种方式控制寄生虫，从而导致疾病。弓形虫在动物细胞内制造生长所需的许多物质，但它也能够清除用于自身目的的各种材料。该研究计划旨在研究寄生虫如何制造或获取其质膜（将寄生虫细胞内部与外部环境分开的脂肪屏障）的重要成分——鞘脂。这将帮助我们了解弓形虫如何在动物细胞内生长以及它随后如何引起疾病。此外，观察到弓形虫（和其他顶端复合物）中制造鞘脂所需的一些机制非常不寻常，这可能最终允许开发针对这些生物体的新药物。

项目成果

Turning up the heat on tropical parasites

加大对热带寄生虫的加热力度

• 期刊: BBSRC Business
• 作者: Paul Denny (Editor)

The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target

• DOI: 10.1016/j.molbiopara.2009.06.002
• 发表时间: 2009-11-01
• 期刊: MOLECULAR AND BIOCHEMICAL PARASITOLOGY
• 影响因子: 1.5
• 作者: Mina, John G.;Pan, Ssu-Ying;Denny, Paul W.
• 通讯作者: Denny, Paul W.

Sphingolipid synthesis and scavenging in the intracellular apicomplexan parasite, Toxoplasma gondii.

• DOI: 10.1016/j.molbiopara.2012.11.007
• 发表时间: 2013-01
• 期刊: MOLECULAR AND BIOCHEMICAL PARASITOLOGY
• 影响因子: 1.5
• 作者: Pratt, Steven;Wansadhipathi-Kannangara, Nilu K.;Bruce, Catherine R.;Mina, John G.;Shams-Eldin, Hosam;Casas, Josefina;Hanada, Kentaro;Schwarz, Ralph T.;Sonda, Sabrina;Denny, Paul W.
• 通讯作者: Denny, Paul W.

Functional and phylogenetic evidence of a bacterial origin for the first enzyme in sphingolipid biosynthesis in a phylum of eukaryotic protozoan parasites.

• DOI: 10.1074/jbc.m117.792374
• 发表时间: 2017-07-21
• 期刊: The Journal of biological chemistry
• 作者: Mina JG;Thye JK;Alqaisi AQI;Bird LE;Dods RH;Grøftehauge MK;Mosely JA;Pratt S;Shams-Eldin H;Schwarz RT;Pohl E;Denny PW
• 通讯作者: Denny PW

A plate-based assay system for analyses and screening of the Leishmania major inositol phosphorylceramide synthase.

用于分析和筛选利什曼原虫主要肌醇磷酸神经酰胺合酶的基于板的测定系统。

• DOI: 10.1016/j.biocel.2010.06.008
• 发表时间: 2010
• 期刊: The international journal of biochemistry & cell biology
• 作者: Mina JG