Toxoplasma: Sphingolipids in host-parasite interactions syntheses versus scavenging

顶复门是一大群相关的单细胞微生物，在人类和经济上重要的家畜中引起一系列疾病（包括疟疾）。其中之一，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注意，因为弓形虫会导致患者的严重疾病，这些患者对这种入侵生物的防御（免疫反应）已经受损，例如患有获得性免疫缺陷综合征的患者。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磅损失。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，寄生虫可以侵入构成动物身体的几乎任何细胞。然而，在大多数情况下，这种感染不会引起严重的疾病，相反，弓形虫是由动物的免疫反应控制，并退回到大脑或肌肉组织中的囊肿。这些囊肿可以在动物的一生中保留，而不会引起任何问题。然而，受损的（在艾滋病患者中）或未发育的（在未出生的动物中）免疫反应无法以这种方式控制寄生虫，从而导致疾病。在动物细胞内，弓形虫产生许多生长所需的物质，然而，它也能够吸收各种用于自身目的的物质。这项研究计划旨在调查寄生虫如何制造或获得其质膜的重要组成部分（将寄生虫细胞内部与外部环境分开的脂肪屏障）鞘脂。这将有助于我们了解弓形虫如何在动物细胞内生长以及如何随后导致疾病。此外，观察到弓形虫（和其他顶复门）中制造鞘脂所需的一些机器非常不寻常，最终可能会开发针对这些生物体的新药。

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.