Defining the Immunomodulatory Niche of Schistosoma haematobium IPSE

 描述(申请人提供)：仅在撒哈拉以南非洲地区就有大约1.2亿人感染血吸虫。血吸虫成虫是泌尿生殖道血吸虫病的病原体，在整个泌尿生殖道产卵。这些卵子会引起明显的炎症反应，导致与感染相关的人类发病率和死亡率。到目前为止，关于血瘤链球菌如何在许多个体逃避免疫清除和免疫的同时，能够诱导如此强大的免疫反应，人们知之甚少。这种知识的缺乏是由于历史上缺乏血瘤链球菌卵子相关病理的模型和操纵血瘤链球菌寄生虫的遗传工具。提出的实验将探索寄生虫卵子分泌免疫调节蛋白IPSE的血瘤链霉菌同源物的功能。IPSE最初是在曼氏血吸虫中描述的，曼氏血吸虫是引起肝肠血吸虫病的姐妹种。IPSE是曼氏血吸虫卵子分泌最丰富的蛋白质，具有许多已发表的生化功能，其中许多功能是由一位合作研究人员首次描述的。我们的四个机构的合作团队将首先定义血瘤链霉菌IPSE同源物的生化功能。然后，我们将产生IPSE基因表达缺失的转基因血瘤链霉菌株，以确定IPSE在体内的效果。

 DESCRIPTION (provided by applicant): Approximately 120 million individuals are infected with Schistosoma haematobium in sub-Saharan African alone. S. haematobium adult worms, the causative agent of urogenital schistosomiasis, lay eggs throughout the urogenital tract. These eggs induce a pronounced inflammatory response responsible for the human morbidity and mortality associated with infection. To date very little is known about how S. haematobium is able to induce such a robust immune response while evading immune clearance and immunity in many individuals. This lack of knowledge is due to the historical lack of both a model for S. haematobium egg- associated pathology, and genetic tools for manipulation of the S. haematobium parasite. Building on recent advances in the S. haematobium field, this collaborative proposal employs the first published mouse model of S. haematobium induced bladder pathology (generated by the PI), and the first successful approaches for genetic manipulation of S. haemtobium (pioneered by the co-investigators). The experiments proposed will explore the functions of the S. haematobium homolog of the parasite egg- secreted immunomodulatory protein IPSE. IPSE was originally described in S. mansoni, the sister species of schistosome responsible for hepatoenteric schistosomiasis. IPSE is the most abundant S. mansoni egg secreted protein, and has numerous published biochemical functions, many of which were first described by a co-investigator on this proposal. Our collaborative team across four institutions will first define the biochemical functions of the S. haematobium IPSE homologue. We will then generate genetically modified S. haematobium strains with deficient IPSE gene expression to determine the effects of IPSE in vivo. Achievement of the aims of this proposal would represent key milestones for S. haematobium research, including, to our knowledge, the first studies on S. haematobium-derived immunomodulatory proteins and the first use of transgenic S. haematobium strains to determine the function of an S. haematobium protein in vivo.