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

由多种微生物引起的并发感染被称为“多发性寄生虫病”，是家畜和野生动物中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与动物体内多寄生虫环境中的寄生虫相互作用。**宿主免疫反应可以分两个阶段考虑。第一种是先天反应，是即刻的、非特定的和短暂的。第二种是适应性反应，这种反应是延迟的，但更具体地说，它会产生“免疫记忆”，通过这个过程，免疫系统可以更有效地识别第二次感染。然而，尽管与生俱来的反应是短暂的，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扰乱了对其他病原体的先天免疫反应，因此在多寄生性的背景下显著改变了疾病动态。**这项研究计划的目标是：*1.在动物中使用复杂的多寄生性模型，从而帮助将研究结果转化为自然界。*2.描述潜在的慢性感染如何扰乱对新寄生虫感染的先天宿主免疫反应。*3.确定这些改变的宿主免疫反应是否会改变寄生虫本身。**我对两种兽医寄生虫最感兴趣：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混合感染的，特别是在有效治疗蠕虫极其困难的情况下。目前治疗寄生虫的兽药寥寥无几，家畜的抗药性问题日益严重。弓形虫是一种存在于多种哺乳动物体内的寄生虫，给畜牧业造成了巨大的经济损失。蠕虫和弓形虫在加拿大很常见，在那里它们会造成巨大的疾病负担，并且经常在同一生物体中一起观察到。因此，它们代表了在多寄生性背景下研究“真实世界”免疫反应的适当模型。**对肠道蠕虫和弓形虫的多寄生性研究已经表明，当有蠕虫存在时，对弓形虫的免疫记忆不那么有效。然而，潜在的机制仍然不清楚。**我在这笔NSERC发现赠款的五年期间的具体目标是：**1.开发寄生蠕虫/弓形虫多寄生性的相关小鼠模型，代表真实世界的动力学，对家畜或自然环境中的动物的这些感染进行建模。*2.描述兽用寄生虫损害宿主对弓形虫感染的先天免疫的机制。我将专注于两种类型的先天性免疫细胞：自然杀伤细胞(NK)和NKT细胞，这两种细胞都已知能产生解决弓形虫感染所需的分子。*3.评估动物中的慢性蠕虫感染如何改变弓形虫的毒力。**这些研究解决了现实世界中多寄生性背景下宿主与寄生虫相互作用的基本问题。将产生的知识具有广泛的生物学意义，并具有巨大的翻译潜力。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性的免疫可能会对我们未来的兽医疾病管理战略产生深远的影响。

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.