Investigating the molecular and cellular basis of impaired vaccine responses in parasitic worm infection

寄生虫感染折磨着全球约1/4的人口。我们的研究集中在感染2亿人的血吸虫上，其中90%生活在撒哈拉以南非洲。个体血吸虫可以在感染者体内存活多年，这反映了这种寄生虫干扰宿主免疫反应的能力。虽然这可能演变为促进感染的慢性，但它也会导致对包括合并感染和疫苗在内的旁观者挑战的免疫抑制。为了达到这个目的，寄生蠕虫产生各种抑制分子，干扰宿主的免疫。然而，这些分子在血吸虫感染中的身份及其调节宿主免疫的机制尚不清楚。在这个项目中，你将研究血吸虫诱导的免疫抑制的分子和细胞基础，重点是疫苗诱导的免疫反应。由于免疫反应受损与慢性感染（即存在产卵的成虫）密切相关，因此您将验证成虫和/或虫卵产生免疫抑制蛋白以调节免疫细胞激活和疫苗反应的假设。为此，您将首先识别蠕虫和卵子分泌的蛋白质，并利用高通量方法在哺乳动物细胞[2]中重组表达，然后使用体外和体内免疫分析测试这些分子的影响。这将侧重于对模型抗原和继人疫苗卡介苗之后的免疫反应。更深入地了解血吸虫形成慢性感染的分子机制，可能会导致新的抗寄生虫策略，以及在过敏和自身免疫疾病的控制中发现新的候选治疗方法。你将在约克由两位MRC资助的研究人员指导，他们采用互补的方法来研究血吸虫免疫抑制（宿主免疫途径和假定的寄生虫免疫调节分子）。通过与NIBSC（英国国家生物标准与控制研究所）的第三位主管合作，该项目受益匪浅。NIBSC是BCG疫苗接种和结核病小鼠模型方面的专家。总之，该项目将为您提供多种生化技术和体外/体内免疫学方面的广泛培训。该项目适合生物医学、生物化学、生物学或相关学科的毕业生，对免疫学和/或寄生虫学有浓厚的兴趣和背景知识。

Parasitic helminth infections afflict ~1/4 of the global population. Our studies have focused on schistosome parasites that infect >200 million people, 90% of whom live in sub-Saharan Africa. Individual schistosome worms can survive for many years within infected people, and this reflects the parasite's ability to interfere with host immune responses [1]. Whilst this likely evolved to promote infection chronicity, it also causes immune suppression to bystander challenges including co-infections and vaccines. To achieve this, parasitic worms produce a variety of inhibitory molecules that interfere with host immunity. However, the identity of these molecules in schistosome infection and the mechanisms by which they modulate host immunity are not well understood.In this project, you will investigate the molecular and cellular basis of schistosome-induced immune suppression, with a focus on vaccine-induced immune responses. As impaired immune responses are most strongly associated with chronic infection (i.e. in the presence of egg-laying adult worms), you will test the hypothesis that adult worms and/or eggs produce immunosuppressive proteins that modulate immune cell activation and vaccine responses. To do this, you will first identify worm and egg secreted proteins and utilise high-throughput methods of recombinant expression in mammalian cells [2], before testing the impact of these molecules using in vitro and in vivo immunological assays. This will focus on immune responses to both model antigens and following the human vaccine, BCG. Greater understanding of the molecular mechanisms by which schistosomes to establish chronic infection can lead to new anti-parasite strategies as well as the discovery of novel therapeutic candidates in the control of allergic and auto-immune conditions.You will be supervised in York by two MRC funded researchers who take complementary approaches to investigate schistosome immune suppression (host immunological pathways and putative parasite immunomodulatory molecules). The project benefits greatly through collaboration with a third supervisor based at NIBSC (National Institute of Biological Standards and Control, UK) who is an expert in mouse models of BCG vaccination and tuberculosis. Together, this project will provide you with extensive training in multiple biochemical techniques and in vitro/in vivo immunology. The project will be suitable for a graduate in Biomedical Sciences, Biochemistry, Biology or related subjects with a strong interest and background knowledge of immunology and/or parasitology.