Discovering host/parasite interactions during larval development of gastrointestinal nematodes

随着人口的持续增长，世界粮食供应的压力也在增加。为了满足这些需求，饮食中的蛋白质将不成比例地来自肉类产品。在世界范围内，胃肠道线虫（GINs），即寄生蛔虫，是牲畜面临的最大的生产限制因素之一。虽然死亡并不常见，但宿主会受到GIN感染的显著负面影响（例如贫血、体重缺乏增加）。GINs在加拿大的牲畜中无处不在，目前控制它们的方法是不可持续的。据估计，GINs对加拿大畜牧业的负面影响每年造成数亿美元的生产损失和动物健康状况不佳。为了制定新的疾病管理策略，我们迫切需要更好地了解免疫反应，以确定促进寄生虫清除的关键因素。我的研究项目集中在发现GINs是如何成功感染的。我的研究系统是多回Heligmosomoides polygyrus (Hp)，这是一种高度流行的啮齿动物寄生虫，也是家畜GINs的模型。当Hp幼虫被摄入后，它们会进入肠道组织并在其中发育。成虫几天后出现并停留在肠道内。传统的实验室模型很好地描述了对Hp等线虫的免疫反应，但结果往往与实地数据相矛盾。我开发了两种小鼠Hp感染的放牧模型来模拟牧场上牛的感染。我的计划旨在发现为什么宿主免疫不能在这些反映更自然环境的模型中清除寄生虫的机制。有了这笔NSERC发现基金，我们将专注于早期感染事件，并确定它们如何影响感染动态和结果。我们是免疫分析和体内模型方面的专家，我们已经优化了用于慢性感染的模型。我们还将结合转录组学分析（散装和单细胞RNAseq）和新开发的细胞体外3D分析（类器官培养），以了解我们对早期感染事件的新关注。我们将确定Hp幼虫与小鼠宿主相互作用的机制，并了解这些机制如何影响宿主/寄生虫动力学。该项目将建立一个新的相关体外系统来研究家畜寄生虫，并为GIN幼虫发育及其对寄生虫清除的影响提供新的知识。这项工作将为在牲畜中开发“免疫增强剂”的生物技术进步奠定基础，以促进寄生虫的清除，并为选择性育种计划提供有关寄生虫耐药性所需的免疫参数的信息。这对经济有直接的好处，因为目前药物的全面失败可能会使加拿大畜牧业每年损失10亿加元。我们的研究结果将是理解和改善动物健康的重要一步。

As the human population continues to grow, pressures on the world's food supplies increase. To meet these needs, dietary protein is going to disproportionately come from meat products. Worldwide, gastrointestinal nematodes (GINs), parasitic roundworms, are one of the greatest production-limiting factors facing livestock. While death is uncommon, hosts are significantly and negatively affected by GIN infection (e.g. anemia, lack of weight gain). GINs are ubiquitous in Canadian livestock and current approaches to control them are unsustainable. The negative impact of GINs to Canada's livestock industry is estimated in the hundreds of millions of dollars annually in lost production and poor animal health. To develop new disease management strategies, we urgently need a better understanding of the immune response to identify the key factors which promote parasite clearance. My research program is focused on discovering how GINs establish successful infections. My study system is Heligmosomoides polygyrus (Hp), a highly prevalent parasite of rodents and a model for GINs of livestock. When Hp larvae are ingested, they enter the intestinal tissue and develop within. Adults emerge days later and remain in the intestinal tract. Immune responses to nematodes like Hp are well described in traditional laboratory models but results often contradict field data. I have developed two grazing models of Hp infection in mice to simulate cattle infection on pasture. My program seeks to discover the mechanisms that underlie why host immunity fails to clear parasites in these models which reflect more natural settings. With this NSERC Discovery Grant, we will focus on early infection events and determine how they influence infection dynamics and outcome. We are experts in the immunological assays and in vivo models we have optimised for use in chronic infections. We will also incorporate transcriptomic analyses (bulk and single cell RNAseq) and newly developed cellular in vitro 3D assays (organoid cultures) pertinent to understanding our new focus on early infection events. We will identify the mechanisms through which Hp larvae interact with their murine host and understand how these impact host/parasite dynamics. This project will create a new relevant in vitro system to study livestock parasites and provide new knowledge on the still relatively unknown topic of GIN larval development and its impact on parasite clearance. This work will be the foundation for biotechnological advances developing `immune boosters' in livestock to promote parasite clearance and informing selective breeding programs on the immune parameters necessary for parasite resistance. This is of direct benefit to the economy, as the total failure of the current drugs will likely cost the Canadian livestock industry one billion Canadian dollars each year. Our results will be an important step to understanding and improving animal health.