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

描述(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，每年新增200万例，3.5亿人处于危险之中。利什曼病是仅次于疟疾的全球第二大寄生虫致死疾病。由于发展和战争将人们转移到寄生虫出没的地区，利什曼病病例一直在增加。通过沙蝇叮咬传播，这些寄生虫会导致致命的内脏疾病，以及无法愈合和毁容的皮肤、口腔和鼻子疾病。利什曼病的药物疗法有严重的副作用，正在失去疗效，而且还没有开发出实用的疫苗。此外，驻扎在阿富汗和伊拉克的美军中已发生1000多例，甚至可能10000例利什曼病。我们一直在研究墨西哥利什曼原虫在小鼠身上的感染，试图理解为什么小鼠不能愈合，而一种相关的寄生虫，大利什曼原虫，会引起皮肤损伤，可以愈合。由墨西哥乳杆菌引起的人类疾病可能会持续数年。重要的是要了解墨西哥乳杆菌是如何阻止人体杀死寄生虫的，以便开发治疗方法来阻止由利什曼原虫和其他生活在细胞内的病原体(结核病、疟疾和弓形虫病)引起的人类感染中的这种寄生虫机制。我们发现，一种名为IL-10的白细胞蛋白可以阻止人体的保护性免疫反应，并且抗体(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，寄生虫会利用人体自身的抗体来阻止愈合。当感染利什曼原虫时，兔子和小鼠会产生针对一种含有脂肪和糖的分子的抗体，这种分子被称为糖化肌醇磷脂(GIPLs)，但不针对蛋白质(这是抗体的常见目标)。我们将验证我们的假设，即GIPLs是利什曼原虫丰富的表面分子，是阻止愈合的抗体反应的目标。我们还将确定一种名为自然杀伤T(NKT)细胞的不寻常类型的白细胞是否对阻止愈合的免疫反应重要。这些NKT细胞被一种名为CD1的不同寻常的蛋白质激活，CD1参与糖脂(如GIPLs)引发的免疫反应。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微生物引起的感染，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针对利什曼原虫感染的新疫苗的方法。特别是，疫苗可能需要设计成不会引起某些类型的抗体来对抗GIPLs。通过这种方式，我们不仅有助于对免疫系统的基本了解，还有助于生产针对利什曼病和其他隐藏在细胞内的病原体引起的疾病的新疫苗，如弓形虫病、结核病和疟疾。与公共卫生相关：单细胞寄生虫利什曼原虫是仅次于疟疾的全球第二大寄生虫致死杀手，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。了解寄生虫如何防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(一种帮助将糖脂呈现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潜在的其他隐藏在细胞内的病原体的新疗法。

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.