TGF-beta activation by gut dendritic cells: identifying a critical pathway in regulation of chronic parasitic infection

我们的免疫系统的功能是检测并摧毁进入身体的有害病原体。一旦感染，免疫反应迅速被激活，以确保尽快处理威胁。然而，被称为蠕虫寄生虫的病原体可以劫持免疫系统，抑制旨在消除感染的反应，从而允许病原体在体内生存和繁殖。这些所谓的慢性寄生虫感染是主要的世界卫生问题，世界人口的四分之一以上受到影响，主要是在发展中国家。寄生虫感染会造成严重的健康和经济问题，但目前对这种感染的治疗极为有限。因此，科学研究的一个重要领域旨在了解蠕虫如何控制免疫反应，使它们能够在我们体内生存。因此，这项工作将导致确定治疗慢性蠕虫感染的潜在新治疗靶点。我们新的令人兴奋的数据已经确定了在慢性蠕虫感染的发展中至关重要的分子。因此，当免疫系统中的树突状细胞激活一种叫做tgf - β的重要分子的能力降低时，慢性感染就不能在一种重要的人类肠道蠕虫感染的小鼠模型中发展。然而，预防慢性感染发生的原因是完全未知的。本文提出的工作旨在揭示免疫系统中缺乏特定途径导致肠道慢性感染完全保护的原因，并确定参与这种保护的免疫系统细胞和分子。我们还将确定其他类型的寄生虫是否也有这种对感染的抵抗力，或者这种保护是否仅针对感染肠道的蠕虫寄生虫。因此，我们的工作将为寄生虫发展为慢性感染所涉及的免疫分子、细胞和机制提供重要见解，从而确定治疗这些破坏性疾病的潜在新治疗靶点。

Our immune system functions to detect and destroy harmful pathogens that enter the body. Upon infection, immune responses are rapidly activated, to ensure the threat is dealt with as quickly as possible. However, pathogens known as helminth parasites can hijack the immune system to suppress responses aimed at eliminating the infection, therefore allowing the pathogen to live and breed inside the body. These so-called chronic helminth infections are major world health problems, with over one quarter of the world population affected, mostly in developing countries. Infections with helminth parasites cause major health and economic problems, but at present treatments for the infections are extremely limited. A vital area of scientific research therefore aims to understand how helminths control immune responses to allow their survival inside our body. Such work will therefore lead to the identification of potential novel therapeutic targets for treating chronic helminth infection.Our new exciting data has identified important molecules that are critically involved in the development of chronic helminth infection. Hence, when cells of the immune system called dendritic cells have reduced ability to activate an important molecule called TGFbeta, chronic infection cannot develop in a mouse model of an important human gut helminth infection. However, why protection from chronic infection occurs is completely unknown. The work proposed here aims to uncover why lack of a specific pathway in the immune system causes complete protection from chronic infection in the gut, determining the cells and molecules of the immune system involved in such protection. We will also determine whether such resistance from infection is seen for other types of parasites, or whether protection is specific to helminth parasites that infect the gut. Our work will therefore provide important insights into immune molecules, cells and mechanisms that are involved in allowing parasites to develop chronic infection, thus identifying potential novel therapeutic targets for treatment of these devastating diseases.