Infections in complex physical environments: Life and death in the sinuses

长期感染和炎性病症是复杂的宿主-病原体反应，由于反应的多尺度性质以及涉及的许多物理和生物因素，这些反应通常知之甚少。建立实验和概念框架是必要的，以获得这样的复杂系统的预测性理解，并连接到整体的紧急行为的本地的相互作用和反应。这种方法需要跨学科的努力，有可能在生命科学/物理学界面提供前所未有的见解。在这里，我们建议研究慢性鼻窦炎（CRS）作为这种方法的模型。CRS被定义为鼻子和鼻窦的炎症，存在超过12周，影响5-12%的一般人群。CRS不仅大大降低了患者的生活质量，而且还带来了非常高的医疗费用。CRS的发病机制归因于多种“生物”和“物理”因素的组合，即多因素病因学是由各种环境因素与宿主免疫系统之间的功能失调相互作用引起的。此外，细菌生长是CRS的重要因素，但其确切作用一直难以阐明。我们建议研究的“系统”由宿主环境中的细菌群落组成，即宿主窦腔的模型，其特征在于形状和几何形状，先天免疫细胞的粘膜反应，与趋化因子表达和对抗感染的炎症反应有关，以及杯状和纤毛上皮细胞的作用，其不断产生和取代粘液衬里，通常是对微生物感染的有效防御。宿主窦微环境是动态物理，化学和生物因素的独特组合，需要多学科的方法来理解它。随着临床医生在团队中，我们的概念和实验方法来理解这个系统将有助于治疗CRS。我们还期望，这里获得的许多结果将适用于各种其他复杂的生命系统，其中流动，微生物和宿主反应相互作用，例如肠道，肺或泌尿道。由于微生物占据了宿主多细胞生物体的每一个暴露表面，这种方法可以帮助为跨学科理解所有生物学中最重要的相互作用之一铺平道路。

Long-term infections and inflammatory conditions are complex host-pathogen responses that are often poorly understood because of the multi-scale nature of the response and numerous physical and biological factors that are involved. Building experimental and conceptual frameworks is necessary to gain a predictive understanding of such complex systems and to link the local interactions and responses to overall emergent behaviour. This approach, which requires an interdisciplinary effort, has the potential to offer unprecedented insights at the life sciences/physics interface. Here we propose to study chronic rhinosinusitis (CRS) as a model of such an approach. CRS is defined as an inflammation of the nose and paranasal sinuses present for more than 12 weeks and affecting 5-12% of the general population. CRS not only significantly reduces the quality of life of patients but also incurs very high healthcare costs. Pathogenesis of CRS is attributed to a combination of multiple 'biological' and 'physical' factors, i.e. the multifactorial aetiology results from a dysfunctional interaction between various environmental factors and the host immune system. Furthermore, bacterial growth is a significant factor in CRS, but its precise role has been difficult to elucidate. The "system" we propose to study consists of bacterial communities in their host environment, i.e. models of the host sinus cavity, characterised by the shape and geometry, the mucosal response of the innate immune cells, linked to the chemokine expression and inflammatory response against the infection, and the role of goblet and ciliated epithelial cells that constantly generate and displace a mucus lining, ordinarily an effective defence against microbial infections. The host sinus microenvironment is such a unique combination of dynamic physical, chemical and biological factors that understanding it requires a multi-disciplinary approach. With a clinician in the team, our conceptual and experimental approaches to understanding this system will aid in treating CRS. We also expect that many results obtained here will be applicable to a wide variety of other complex living systems, where flow, microbes and host response interact, e.g. gut, lungs or urinary tract. As microbes occupy every exposed surface of their host multi-cellular organisms, this approach can help pave the way for an interdisciplinary understanding of one of the most important interactions in all of biology.