Pneumonia is one of the most common infectious diseases worldwide. The influenza virus can cause severe epidemics, which results in significant morbidity and mortality. Beyond the virulence of the virus itself, epidemiological data suggest that bacterial co-infections are the major cause of increased mortality. In this context, Staphylococcus aureus represents a frequent causative bacterial pathogen. Currently available models have several limitations in the analysis of the pathogenesis of infections, e.g. some bacterial toxins strongly act in a species-specific manner. Human 2D mono-cell culture models often fail to maintain the differentiation of alveolus-specific functions. A detailed investigation of the underlying pathogenesis mechanisms requires a physiological interaction of alveolus-specific cell types. The aim of the present work was to establish a human in vitro alveolus model system composed of vascular and epithelial cell structures with cocultured macrophages resembling the human alveolus architecture and functions. We demonstrate that high barrier integrity maintained for up to 14 d in our model containing functional tissue-resident macrophages. We show that flow conditions and the presence of macrophages increased the barrier function. The infection of epithelial cells induced a high inflammatory response that spread to the endothelium. Although the integrity of the epithelium was not compromised by a single infection or co-infection, we demonstrated significant endothelial cell damage associated with loss of barrier function. We established a novel immune-responsive model that reflects the complex crosstalk between pathogens and host. The in vitro model allows for the monitoring of spatiotemporal spreading of the pathogens and the characterization of morphological and functional alterations attributed to infection. The alveolus-on-a-chip represents a promising platform for mechanistic studies of host-pathogen interactions and the identification of molecular and cellular targets of novel treatment strategies in pneumonia.

中文翻译：

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原发性流感病毒感染后与金黄色葡萄球菌的共感染会导致人肺小片上肺泡模型的内皮损伤。

肺炎是全世界最常见的传染病之一。流感病毒可引起严重的流行病，从而导致很高的发病率和死亡率。除了病毒本身的毒性外，流行病学数据还表明，细菌共感染是死亡率增加的主要原因。在这种情况下，金黄色葡萄球菌是一种常见的致病细菌病原体。当前可用的模型在感染的发病机理分析中有一些局限性，例如某些细菌毒素以物种特异性方式强烈起作用。人类2D单细胞培养模型通常无法维持肺泡特定功能的分化。对潜在发病机制的详细研究需要肺泡特异性细胞类型的生理相互作用。本工作的目的是建立由血管和上皮细胞结构与共培养的类似于人肺泡结构和功能的巨噬细胞组成的人体外肺泡模型系统。我们证明，在包含功能性组织驻留巨噬细胞的模型中，高屏障完整性可维持长达14天。我们表明流动条件和巨噬细胞的存在增加了屏障功能。上皮细胞的感染引起高炎症反应，并扩散到内皮。尽管单个感染或合并感染不会损害​​上皮的完整性，但我们证明了与屏障功能丧失相关的内皮细胞明显受损。我们建立了一个新型的免疫反应模型，该模型反映了病原体与宿主之间的复杂串扰。体外模型允许监测病原体的时空传播以及表征归因于感染的形态和功能改变。肺泡芯片代表了一种有前途的平台，用于宿主-病原体相互作用的机理研究以及鉴定肺炎新治疗策略的分子和细胞靶标。