The Immunology Of Polyparasitism: How Underlying Chronic Worm Infections Affect Immune Responses To Veterinary Parasites

由多种微生物引起的同时感染被称为“多重寄生虫病”，是家畜和野生动物因传染病造成的损失增加的原因。我们目前对感染免疫的大部分知识都是从使用简化的单一感染模型的研究中产生的。我的总体研究目标是发现宿主免疫系统如何在动物体内的多寄生环境中与寄生虫相互作用。**宿主免疫反应可分为两个阶段。第一种是先天反应，它是即时的、非特异性的、短暂的。第二种是适应性反应，这种反应是延迟的，但更具体，产生“免疫记忆”，通过这个过程，免疫系统可以在第二次更有效地识别感染。然而，尽管先天反应是短暂的，但它会影响随后的适应性反应的性质。我们的中心假设是潜在的慢性蠕虫感染强烈破坏了对其他病原体的先天免疫反应，因此在多寄生的背景下显著改变了疾病动态。**这个研究项目的目的是：*1。在动物中采用复杂的多寄生模型，从而帮助将研究结果转化为自然世界。表征潜在的慢性感染如何破坏宿主对新寄生虫感染的先天免疫反应。* 3。以确定这些改变的宿主免疫反应是否改变了寄生虫本身。**我最感兴趣的是两种兽医寄生虫：肠道蠕虫和单细胞球虫。肠道蠕虫引起慢性感染，强烈改变宿主的免疫系统，使宿主更有可能感染另一种寄生虫。事实上，大多数感染肠道蠕虫的动物都是合并感染的，特别是因为有效治疗蠕虫是极其困难的。很少有兽药可用于治疗寄生虫，而耐药性在家畜中是一个日益严重的问题。弓形虫球虫是一种存在于大多数哺乳动物体内的寄生虫，对畜牧业造成重大经济损失。蠕虫和弓形虫在加拿大很常见，它们会造成严重的疾病负担，并且经常在同一生物体中被观察到。因此，它们代表了在多寄生背景下研究“真实世界”免疫反应的适当模型。**肠道蠕虫和弓形虫的多寄生研究已经表明，当蠕虫存在时，对弓形虫的免疫记忆效果较差。然而，潜在的机制仍然不清楚。**我在这项NSERC发现资助的五年期间的具体目标是：**1。目的：建立相应的寄生虫/T小鼠模型。弓形虫多寄生，代表了现实世界的动态，模拟了家畜或自然环境中动物的这些感染。表征兽医寄生虫损害宿主对弓形虫感染的先天免疫的机制。我将重点介绍两种类型的先天免疫细胞：自然杀伤细胞（NK）和NKT细胞，这两种细胞都能产生解决弓形虫感染所需的分子。评估动物慢性虫感染如何改变弓形虫毒力。**这些研究解决了在多重寄生的现实环境中宿主-寄生虫相互作用的基本问题。所产生的知识具有广泛的生物学意义，并具有重要的转化潜力。鉴于我们缺乏针对这些感染的有效兽医治疗/疫苗以及我们对自然环境中疾病动态的有限了解，更好地了解宿主对多寄生的免疫可能对我们未来的兽医疾病管理策略产生深远的影响。

Concurrent infections caused by multiple microbes are known as `polyparasitisms' and are responsible for increased losses due to infectious diseases in domestic livestock and wildlife. Most of our current knowledge of immunity to infections has been generated from studies using simplified mono-infection models. My overall research goal is to discover how the host immune system interacts with parasites in polyparasitic environments within animals.**The host immune response can be considered in two phases. The first, the innate response, is immediate, non-specific, and short-lived. The second, the adaptive response, is delayed but more specific, generating `immune memory', a process by which the immune system can recognise an infection more effectively the second time. However, although the innate response is short-lived, it influences the nature of the ensuing adaptive response. Our central hypothesis is that underlying chronic worm infections strongly disrupt innate immune responses to other pathogens, therefore significantly altering disease dynamics in the context of polyparasitism. **The aims of this research program are: *1. To employ complex polyparasitism models in animals, thus helping translate findings to the natural world.*2. To characterise how underlying chronic infections disrupt innate host immune responses to new parasitic infections. *3. To determine whether these altered host immune responses modify the parasite itself.**I am most interested in two types of veterinary parasites: intestinal worms and single-celled coccidians. Intestinal worms cause chronic infections that strongly alter the host immune systems such that hosts are more likely to become infected with another parasite. Indeed, most animals infected with intestinal worms are co-infected, especially since effectively treating worms is extremely difficult. Few veterinary drugs are available to treat parasitic worms, and drug-resistance is an increasing problem in domestic animals. The coccidian Toxoplasma gondii is a parasite found in most types of mammals, which causes significant economic losses to the livestock industry. Both worms and T. gondii are common in Canada where they cause significant disease burden and are often observed together in the same organism. As such they represent appropriate models for studying `real-world' immune responses in the context of polyparasitism.**Polyparasitism studies with intestinal worms and T. gondii have already shown that the immune memory to T. gondii is less effective when worms are present. However, the underlying mechanisms remain obscure. **My specific objectives in the five year period of this NSERC discovery grant are:**1. To develop a relevant mouse model of parasitic worm/T. gondii polyparasitism, representative of real-world dynamics, that models these infections in domestic animals or animals in the natural environment.*2. To characterize the mechanisms by which veterinary parasitic worms impair host innate immunity to T. gondii infection. I will focus on two types of innate immune cell: Natural Killer (NK) and NKT cells, both known to produce molecules required to resolve T. gondii infection.*3. To assess how chronic worm infection in animals modifies T. gondii virulence.**The studies address the fundamental questions of host-parasite interactions, in the real-world setting of polyparasitism. The knowledge to be generated is of broad biological interest, and carries significant translational potential. In light of our lack of effective veterinary treatments/vaccines for these infections and our limited understanding of disease dynamics in natural environments, a better understanding of host immunity to polyparasitism may have a profound impact on our future veterinary disease management strategies.