Immunodynamics and infectious disease risk in the natural environment

每个人对传染病的反应各不相同，无论是人类、牲畜还是野生动物。为了保护人类和兽医的健康，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免疫系统在机制层面上的工作提供了巨大的洞察力，但为什么一些人更容易受到感染这一更大的问题不能通过这一途径解决。在自然环境中，野生动物容易受到多种病原体的感染，必须应对这些感染，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。同样的事情也适用于世界上较贫穷地区的人类。这些相互冲突的压力可能导致应对感染的不同策略。首先，可能会产生免疫反应来清除感染；我们称之为抵抗力。但这可能会以免疫反应本身(免疫病理学)对宿主组织造成的损害为代价。或者，减少感染造成的损害--称为耐受性--可能更好，特别是如果一个人不断地从环境中重新感染的话。免疫反应的类型在一定程度上取决于个人接触的病原体的类型，但在表面上相似的情况下，个人对感染的反应却不同，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、既往感染史和肠道细菌组成方面会有所不同。所有这些都可能影响它们在感染后产生的免疫反应的类型或强度。因此，我们的目标是阐述自然人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)和健康的后果。这项研究的好处将是确定使个人或多或少容易感染和疾病的个人类型和环境环境。这将有助于保护面临疾病威胁的自然种群，减轻人畜共患传染病(从野生动物种群传染给人类的感染)，并增加对人类免疫的了解。实验室啮齿动物不能给我们所需要的答案，我们也不能出于实际和伦理的原因来研究人类种群。相反，为了实现我们的目标，我们将利用对田鼠的长期生态学研究，田鼠是一种啮齿动物物种，在英国大量存在，感染了多种病原体，我们现在已经为其生成了基因组序列和免疫学分析，以衡量自然环境中免疫反应的关键成分。因此，这是一个模型系统，将揭示一般情况下对传染病反应的差异。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，以了解遗传和环境是如何塑造免疫反应的，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.