Mechanisms of host:parasite immune regulation during Schistosoma mansoni infection

血吸虫病是一种广泛流行的、极具破坏性的寄生虫病，影响着亚热带地区较贫穷国家的2.2亿多人，每年估计造成20万人死亡。尽管它很重要，但目前还没有疫苗可用。血吸虫寄生虫与受感染的水接触后进入人体，并在血液中停留，在那里它们不断接触宿主免疫系统。为了生存，它们开发了复杂的免疫逃逸机制，多年来保护它们免受宿主免疫系统的攻击。然而，寄生虫用来抑制免疫的蛋白质的特性仍不清楚。对动物模型和生活在血吸虫病流行地区的患者的研究表明，随着时间的推移，建立对这种疾病的保护性免疫是可能的；然而，宿主免疫系统靶向提供这种保护的寄生虫蛋白尚未被发现。这项研究项目的主要目标是确定宿主抗体靶向的寄生虫蛋白以提供免受感染的保护，以及寄生虫用来颠覆宿主免疫反应的蛋白。存在于寄生虫外表面或由寄生虫分泌到宿主血液中的蛋白质被认为是这两种功能的主要参与者，因为它们可以直接与宿主抗体接触，并可以直接与其免疫细胞相互作用。利用实验室最近生产的100多种重组蛋白的大量收集，我们将进行血清学和生化研究，这些重组蛋白概括了曼氏血吸虫寄生虫表面自然发现的或由其分泌的蛋白质的形态和功能。我们将使用对曼氏沙门氏菌感染有抵抗力的小鼠和巴西人的血清，并将它们暴露在重组寄生虫蛋白中，以确定与长期感染曼氏沙门氏菌的人相比，这些具有抵抗力的人是否会产生针对特定寄生虫蛋白的抗体。我们还将使用一些生化技术来确定哪些寄生虫蛋白质能够与人类免疫细胞结合，以及它们如何干扰调节寄生虫感染免疫反应的蛋白质的功能。通过确定宿主免疫系统在自然抵抗感染的背景下所针对的寄生虫蛋白以及那些在免疫调节中发挥作用的寄生虫蛋白，我们希望揭示新的候选蛋白，这些候选蛋白可以开发成针对这种广泛且高度病态的寄生虫病的急需的血吸虫病疫苗靶点。

Schistosomiasis is a widespread and highly debilitating parasitic disease affecting over 220 million people in the poorer countries of the sub-tropical areas and causing the death of an estimated 200,000 individuals every year. Despite its importance, no vaccine is available. Schistosoma parasites enter the human body after contact with infected water and take residency in the bloodstream, where they are constantly exposed to the host immune system. To survive, they have developed sophisticated mechanisms of immune escape that protects them from the host immune system for many years. However, the identity of the proteins used by the parasite to suppress immunity remains unknown. Study of animal models and of patients living in areas where schistosomiasis is endemic suggests that it is possible to build up a protective immunity to the disease over time; however, the parasite proteins that the host immune system targets to confer this protection have not yet been found. The main goal of this research project is to identify the parasite proteins targeted by host antibodies to confer protection from infection as well as the proteins that the parasite uses to subvert its host's immune response. Proteins present on the outer surface of the parasite or secreted by the parasite into its host's bloodstream are believed to be the main actors of both of these functions as they are directly accessible to the host antibodies and can directly interact with its immune cells. Using a large and recent collection of over one hundred recombinant proteins produced in the laboratory, which recapitulate the shape and function of the proteins naturally found at the surface of or secreted by the Schistosoma mansoni parasite, we will perform serological and biochemical studies. We will use sera from both mice and Brazilian individuals who are resistant to S. mansoni infection and expose them to the recombinant parasite proteins to determine whether these resistant individuals produce antibodies against specific parasite proteins compared to individuals who are chronically infected with S. mansoni. We will also use some biochemical techniques to identify which parasite proteins are able to bind to human immune cells and how they interfere with the function of proteins that regulate the immune response to parasite infection. By identifying the parasite proteins targeted by the host immune system in the context of natural resistance to infection and those that play a role in immunoregulation, we hope to reveal new candidates that can be developed into much-needed schistosomiasis vaccine targets against this widespread and highly-morbid parasitic disease.