Dynamics of Susceptibility and Transmission of Campylobacter jejuni in Chickens

空肠弯曲杆菌是英国细菌性食物中毒的主要原因，据信其最大来源是受污染的家禽产品。因此，监管当局的主要重点是采取措施，限制商业禽群中弯曲杆菌阳性鸟类的数量。观察弯曲杆菌在不同禽群中的负担的研究为禽群水平上的传播动态提供了重要的见解。特别是，几乎不可能区分鸡群的弯曲杆菌水平较低是由于个体更难以定植还是由于个体之间的传播率较低。然而，仅从观测数据很难区分造成任何观测到的差异的机制。对照动物挑战实验可以系统地解决这些问题。传统上，这需要进行单独的对照实验，以独立评估传播和易感性。最近的统计模型——基于传播的数学模型并由CIDC开发——提供了一种新的方法，可以通过单一实验同时估计易感性和传播。在这个项目中，我们将进一步发展这一理论，并推广这种方法，以减少为实现既定科学目标而需要杀死的实验动物的数量。虽然这项研究是专门针对弯曲杆菌在鸡体内的定植进行的，但我们预计这一理论将更普遍地适用，并有可能减少在广泛的宿主-病原体系统调查中使用的动物数量。数学模型也有助于我们更有效地理解和利用监测数据，并告知我们对定植禽群的生物机制的理解。我们在牛津大学的合作者生成的一组独特的数据表明，在肉鸡生产中，当禽类生长超过平均屠宰年龄（30-40天）时，它们可能会自然地开始清除弯曲杆菌。我们开始使用数学模型来评估这一假设，并确定最简单的可能机制集，以解释这一迷人的新数据集。该数据集还提供了弯曲杆菌不同菌株多样性的快照，以及它如何随时间变化。了解不同菌株的宿主内部和宿主之间的竞争将有助于开发新的合理干预措施来减少定植。我们将利用这一独特的资源开始开发一个框架，通过该框架可以描述不同菌株的竞争动态，并改进未来研究的设计。高通量测序正迅速变得足够快速和廉价，我们将能够研究不同菌株的种群在自然传播条件下如何随时间演变。我们建议开始理论的发展，这将有助于收集和分析这些数据，以提高我们对这种重要的人畜共患病原体的基本定植生物学的理解。

Campylobacter jejuni is the leading cause of bacterial food poisoning in the UK, the largest source of which is believed to be contaminated poultry products. For this reason, the primary focus of regulatory authorities is directed towards measures that will limit the numbers of campylobacter-positive birds in commercial flocks. Studies that observe the burden of Campylobacter within different flocks provide important insights into the dynamics of transmission at the flock level. In particular it is almost impossible to distinguish whether flocks have lower levels of Campylobacter due to the individuals being more difficult to colonise or due to the rate of transmission between individuals being lower. However, from observational data alone it is difficult to distinguish the mechanisms responsible for any observed differences. Controlled animal challenge experiments can resolve these questions systematically. Traditionally this would require separate controlled experiments to be carried out to assess transmission and susceptibility independently. Recent statistical models - based on mathematical models of transmission and developed by the CIDC - offer a new approach whereby susceptibility and transmission can be simultaneously estimated from a single experiment. In this project we will develop this theory further and promote this approach that should lead to reductions in the number of experimental animals required to be killed to achieve a given scientific objective. Although this research is being developed specifically with regards to the colonisation of chickens with Campylobacter, we anticipate that this theory will be more generally applicable and has the potential to reduce the number of animals used in the investigation of a broad range of host-pathogen systems. Mathematical models are also useful for helping us to understand and utilise surveillance data more effectively and inform our understanding of the biological mechanisms in action with colonised flocks. A unique data set generated by our collaborators at the University of Oxford suggests that birds may naturally begin to clear Campylobacter when they have grown beyond the average slaughter-age of 30-40 days in Broiler production. We set out to use mathematical models to assess this hypothesis and determine the simplest possible set of mechanisms that can explain this fascinating new data set. This data set also provides a snapshot of the diversity of different strains of Camyplobacter and how it changes over time. Understanding the within- and between-host competition of different strains of bacteria will allow the development of new rational interventions to reduce colonisation. We will use this unique resource to begin to develop a framework by which the competition dynamics of different strains can be described, and the design of future studies improved. High-throughput sequencing is rapidly becoming fast and cheap enough that we will be able to study how the population of different strains evolves over time under natural transmission conditions. We propose to begin the development of theory that will facilitate the collection and analysis of such data to improve our understanding of the basic colonisation biology of this important zoonotic pathogen.