The Role of Glycolipids and CD1 in the Immunology of Leishmania Infection

描述（由申请人提供）：全世界有1200万人感染单细胞寄生虫利什曼原虫，每年有200万新发病例，3.5亿人处于危险之中。利什曼病是世界上第二大杀手，仅次于寄生虫引起的疟疾。利什曼病病例一直在增加，由于发展和战争，人们进入寄生虫出没的地区。这些寄生虫通过白蛉叮咬传播，引起内脏器官的致命疾病以及皮肤、口腔和鼻子的不愈合和毁容疾病。利什曼病的药物治疗具有严重的副作用，并且正在失去疗效，并且尚未开发出实用的疫苗。此外，驻扎在阿富汗和伊拉克的美国军队中发生了1,000多起，甚至可能是10,000起利什曼病病例。我们一直在研究感染墨西哥利什曼原虫的小鼠，试图了解为什么小鼠不愈合，而一个相关的寄生虫，L。严重的，会导致皮肤损伤，但会愈合。L.墨西哥可以持续数年。重要的是要了解L。墨西哥利什曼原虫阻止人体杀死寄生虫，以开发治疗方法，阻止这种寄生虫机制在人类感染引起的利什曼原虫和其他病原体，生活在细胞内（结核病，疟疾和弓形虫病）。我们发现，一种称为IL-10的白色血细胞蛋白质可以阻止人体的保护性免疫反应，抗体（帮助对抗感染的蛋白质）可以附着在利什曼原虫的表面，诱导IL-10的产生。因此，人体自身的抗体被寄生虫利用，以防止愈合。当感染利什曼原虫时，兔子和小鼠会产生一种称为糖肌醇磷脂（GIPL）的脂肪和糖分子的抗体，但不会产生蛋白质（这是抗体的通常目标）。我们将检验我们的假设，即GIPL（利什曼原虫丰富的表面分子）是阻止愈合的抗体反应的靶点。我们还将确定一种称为自然杀伤T（NKT）细胞的不寻常类型的白色血细胞是否对这种阻止愈合的免疫反应很重要。这些NKT细胞被一种称为CD1的不寻常蛋白质激活，这种蛋白质参与糖脂（如GIPL）引起的免疫反应。CD1和NKT细胞在感染中的作用方式尚不清楚。 虽然人们早就知道抗体反应不能治愈隐藏在细胞内的生物体引起的感染，但现在越来越清楚的是，这些抗体可以阻止愈合。我们相信，了解抗体可以阻止利什曼病愈合的方式可能有助于我们确定评估抗利什曼原虫感染的新疫苗的方法。特别是，可能需要设计疫苗，使其不会引起针对GIPL的某些类型的抗体。通过这种方式，我们不仅可以对免疫系统的基本理解做出贡献，而且还可以生产针对利什曼病和由隐藏在细胞内的其他病原体引起的疾病（如弓形虫病，结核病和疟疾）的新疫苗。公共卫生相关性：单细胞寄生虫利什曼原虫是世界上仅次于疟疾的第二大杀手，每年感染200多万人，任何时候都有1200万人感染，3.5亿人处于危险之中。了解寄生虫如何阻止宿主消除的机制对于开发疫苗和药物疗法至关重要。确定糖脂（附着在脂肪上的糖）和CD1（一种帮助将它们呈递给免疫系统的哺乳动物蛋白质）如何抑制免疫反应，将有助于开发针对利什曼病和隐藏在细胞内的潜在其他病原体的新疗法。

DESCRIPTION (provided by applicant): Worldwide 12 million people are infected with the single-celled parasite Leishmania, with 2 million new cases each year, and 350 million people at risk. Leishmaniasis is the number two killer worldwide after malaria for death caused by parasites. Leishmaniasis cases have been increasing due to development and wars moving people into parasite-infested areas. Spread by sandfly bites, these parasites cause fatal disease of the internal organs as well as non-healing and disfiguring diseases of the skin, mouth, and nose. Drug therapies for leishmaniasis have severe side effects and are losing their curative effect, and no practical vaccine has yet been developed. In addition, over 1,000, and possibly 10,000, cases of leishmaniasis have occurred in the U.S. military stationed in Afghanistan and Iraq. We have been studying Leishmania mexicana infection in mice, attempting to understand why mice do not heal, whereas a related parasite, L. major, causes skin lesions that do heal. Human disease caused by L. mexicana can last for years. It is important to understand how L. mexicana stops the body from killing the parasite, in order to develop therapies to block this parasite mechanism in human infections caused by Leishmania and other pathogens that live inside cells (tuberculosis, malaria, and toxoplasmosis). We found that a white blood cell protein, called IL-10, prevents the body's protective immune response and that antibodies (proteins made to help fight infection) can attach to the surface of Leishmania parasites inducing IL- 10 production. Thus the body's own antibodies are exploited by the parasite to prevent healing. When infected with Leishmania, rabbits and mice develop antibodies to a type of molecule with fat and sugars called glycoinositol phospholipids (GIPLs), but not to proteins (which are the usual targets of antibodies). We will test our hypothesis that GIPLs, abundant surface molecules of Leishmania, are the targets of antibody responses that prevent healing. We will also determine if an unusual type of white blood cell called natural killer T (NKT) cells are important to this immune response that prevents healing. These NKT cells are activated by an unusual protein called CD1, which is involved in immune responses provoked by glycolipids (like GIPLs). The way in which CD1 and NKT cells work in infection is not well understood. Although it has long been known that antibody responses do not cure infections caused by organisms that hide inside cells, it is now becoming clear that these antibodies can prevent healing. We believe that understanding the ways that antibodies can prevent healing of leishmaniasis may help us to determine ways to evaluate new vaccines against Leishmania infection. In particular, vaccines may need to be designed that do not cause certain types of antibodies to be made against GIPLs. In this way we may contribute not only to a basic understanding of the immune system but also, to the production of new vaccines against leishmaniasis and diseases caused by other pathogens that hide inside cells, like toxoplasmosis, tuberculosis and malaria. PUBLIC HEALTH RELEVANCE: The single-celled parasite Leishmania, which is the number two killer worldwide after malaria for death caused by parasites, infects over two million people each year, with 12 million infected at any one time, and 350 million people at risk. Understanding the mechanisms of how the parasite prevents elimination by the host is crucial for developing vaccines and drug therapies. Determining how glycolipids (sugars attached to fat) and CD1, a mammalian protein that helps present them to the immune system, work to suppress an immune response will aid in developing novel treatments for leishmaniasis and potentially other pathogens that hide inside cells.