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

多寄生的免疫学：潜在的慢性蠕虫感染如何影响对兽医寄生虫的免疫反应

• 批准号: RGPIN-2014-04305
• 负责人: Finney, Constance
• 金额: $ 2.55万
• 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: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=566432
• 关键词: Immunology; Polyparasitism; How; Underlying; Chronic

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.

由多种微生物引起的并发感染被称为“多寄生虫病”，并且是由于家畜和野生动物中的传染病而导致损失增加的原因。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。宿主免疫应答可以分为两个阶段。第一种是先天反应，是即时的、非特异性的和短暂的。第二种是适应性反应，它被延迟但更具体，产生“免疫记忆”，这是一个免疫系统可以第二次更有效地识别感染的过程。然而，虽然先天反应是短暂的，它影响了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对其他病原体的先天免疫反应，因此在多寄生的背景下显着改变疾病动态。本研究的目的是：1。在动物中采用复杂的多寄生模型，从而帮助将发现转化为自然世界。2.阐明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极其困难。很少有兽药可用于治疗寄生蠕虫，抗药性是家畜中日益严重的问题。弓形虫是一种寄生在大多数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T.弓形虫在加拿大很常见，在那里它们会造成重大的疾病负担，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的背景下研究“真实世界”免疫反应的适当模型。肠道蠕虫和T. gondii的研究已经表明，T.当有蠕虫存在时，弓形虫的效果较差。然而，潜在的机制仍然不清楚。我在这NSERC发现补助金的五年期间的具体目标是：1。建立相应的小鼠寄生虫/T.弓形虫多寄生，代表真实世界的动态，模拟家畜或自然环境中动物的这些感染。2.探讨兽用寄生蠕虫损害宿主对T.弓形虫感染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分解T细胞所需的分子。弓形虫感染3.为了评估动物慢性蠕虫感染如何改变T。弓形虫毒力这些研究解决了宿主-寄生虫相互作用的基本问题，在现实世界中的多寄生。所产生的知识具有广泛的生物学意义，并具有重大的翻译潜力。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了解有限，更好地了解宿主对多寄生虫的免疫力可能对我们未来的兽医疾病管理策略产生深远影响。