Discovering host/parasite interactions during larval development of gastrointestinal nematodes

发现胃肠道线虫幼虫发育过程中宿主/寄生虫的相互作用

• 批准号: RGPIN-2022-03130
• 负责人: Finney, Constance
• 金额: $ 3.5万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744730
• 关键词: Discovering; host; parasite; interactions; during

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.

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，膳食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（GIN），寄生蛔虫，是牲畜面临的最大生产限制因素之一。虽然死亡并不常见，但宿主会受到GIN感染的显著和负面影响（例如贫血，体重增加不足）。GIN在加拿大牲畜中无处不在，目前控制它们的方法是不可持续的。据估计，GIN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良。为了开发新的疾病管理策略，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GIN如何建立成功的感染。我的研究系统是Heligmosomoides polygyrus（Hp），一种高度流行的啮齿动物寄生虫和家畜GIN的模型。当幽门螺杆菌幼虫被摄入时，它们进入肠道组织并在其中发育。成虫在几天后出现并留在肠道中。在传统的实验室模型中很好地描述了对线虫（如Hp）的免疫反应，但结果往往与现场数据相矛盾。我已经开发了两个放牧模型的Hp感染小鼠，以模拟牧场上的牛感染。我的项目旨在发现为什么宿主免疫不能清除这些模型中的寄生虫的机制，这些模型反映了更自然的环境。有了这个NSERC发现补助金，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。 我们是免疫学检测和体内模型方面的专家，我们已优化用于慢性感染。我们还将整合转录组学分析（批量和单细胞RNAseq）和新开发的细胞体外3D测定（类器官培养物），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/寄生虫的动态。该项目将创建一个新的相关体外系统来研究牲畜寄生虫，并提供关于GIN幼虫发育及其对寄生虫清除影响的相对未知主题的新知识。这项工作将成为生物技术进步的基础，在牲畜中开发“免疫增强剂”，以促进寄生虫清除，并为选择性育种方案提供关于寄生虫抗性所需免疫参数的信息。这对经济有直接的好处，因为目前药物的完全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了解和改善动物健康的重要一步。