Immunodynamics and infectious disease risk in the natural environment

无论是人类、牲畜还是野生动物，个体对传染病的反应各不相同。为了保护人类和兽医的健康，为了保护野生动物，我们需要了解是什么让一些人比其他人更容易感染疾病。对实验室小鼠的研究为了解免疫系统如何在机制层面上工作提供了很好的见解，但更大的问题是，为什么有些人更容易受到感染，这一途径无法解决。在自然环境中，野生动物容易受到多种病原体的感染，必须在应对这些感染的同时，还要应对环境压力以及寻找食物、寻找配偶和繁殖的压力。类似的事情仍然可以在世界上较贫穷地区的人类身上说出来。这些相互冲突的压力可能导致应对感染的不同策略。首先，可以产生免疫反应来清除感染；我们称之为阻力。但这可能会以免疫反应本身对宿主组织的损害为代价（免疫病理学）。或者，最好减少感染造成的损害——被称为耐受性——特别是如果一个人不断地从环境中重新获得感染。免疫反应的类型部分取决于个体所接触的病原体的类型，但在表面上相似的情况下，个体对感染的反应却有所不同，有些人在抵抗或耐受感染方面肯定比其他人差。自然种群中的个体在遗传、营养水平、感染史和肠道细菌组成方面存在差异。所有这些都可能影响他们在感染后产生的免疫反应的类型或强度。因此，我们的目标是详细阐述自然种群中免疫变异的遗传和环境驱动因素，以及这种变异对感染、疾病（感染的临床症状）和健康的影响。这项研究的好处将是确定使个人或多或少易受感染和疾病影响的个人类型和环境情况。这将有助于保护受疾病威胁的自然种群，减轻人畜共患感染（从野生动物种群传播给人类的感染），并增进对人类免疫力的了解。实验室里的啮齿动物不能给我们所需的答案，我们也不能因为实际和道德的原因而研究人类种群。相反，为了实现我们的目标，我们将利用对田鼠的长期生态研究，田鼠是一种在英国丰富的啮齿动物物种，感染了多种病原体，我们现在已经生成了基因组序列和免疫学分析，以测量自然环境中免疫反应的关键成分。因此，它是一个模型系统，将阐明对传染病反应的变化。我们将从现场进行密集采样，并对多种免疫反应进行实验室分析，然后对调节网络进行计算分析，以了解免疫反应如何受到遗传和环境的影响，以及这些反应对健康和健身的影响。

Individuals vary in their response to infectious disease, be they humans, livestock or wild animals. To protect human and veterinary health, and to conserve wildlife, we need to understand what makes some individuals more vulnerable to disease than others. Studies of laboratory mice have provided great insight into how the immune system works at a mechanistic level, but the bigger question of why some individuals are more vulnerable to infection cannot be resolved by this route. In the natural environment, wild animals are subject to infection by multiple pathogens and must cope with these infections while also coping with environmental stress and the pressures of finding food, finding a mate and reproducing. Similar things can still be said of humans in the poorer parts of the world. These conflicting pressures can lead to different strategies to cope with infection. First, immune responses may be produced to clear an infection; we refer to this as resistance. But this can come at a significant cost in damage to host tissue by the immune response itself (immunopathology). Alternatively, it may be better to reduce the damage caused by the infection - referred to as tolerance - particularly if an individual is constantly re-acquiring infection from the environment. The type of immune responses made depend in part on the type of pathogen to which an individual is exposed, but individuals in apparently similar circumstances nonetheless differ in their responses to infection, and some are certainly worse than others at either resisting or tolerating infection. Individuals within a natural population will differ in their genetics, level of nutrition, prior history of infection, and in the composition of their gut bacteria. All of these may affect the type or strength of immune responses that they make following infection. Our aim, therefore, is to elaborate the genetic and environmental drivers of immunological variation in natural populations and the consequences of this variation for infection, disease (clinical symptoms of infection) and health. The benefits of this research will be to identify the types of individuals, and the environmental circumstances, that make individuals more or less vulnerable to infection and disease. This will help to conserve natural populations threatened with disease, to mitigate against zoonotic infections (infections passed from wildlife populations to humans), and to increase understanding of human immunity. Laboratory rodents cannot give us the answers we require, and we cannot study human populations for a combination of practical and ethical reasons. Rather, to achieve our aims we will exploit a long-standing ecological study of field voles, a rodent species that is abundant in the UK, infected with multiple pathogens and for which we have now generated a genome sequence and immunological assays to measure key components of the immune response in the natural environment. It is thus a model system that will cast light on variation in responses to infectious disease generally. We will perform intensive sampling from the field, and laboratory analysis of multiple immune responses, followed by computational analysis of regulatory networks to understand how the immune responses are shaped by genetics and environment and the consequences of these responses for health and fitness.