Viral-induced exacerbation of asthma remains a major cause of hospitalization and mortality. New human-relevant models of the airways are urgently needed to understand how respiratory infections may trigger asthma attacks and to advance treatment development. Here, we describe a new human-relevant model of rhinovirus-induced asthma exacerbation that recapitulates viral infection of asthmatic airway epithelium and neutrophil transepithelial migration, and enables evaluation of immunomodulatory therapy. Specifically, a microengineered model of fully differentiated human mucociliary airway epithelium was stimulated with IL-13 to induce a T-helper cell type 2 asthmatic phenotype and infected with live human rhinovirus 16 (HRV16) to reproduce key features of viral-induced asthma exacerbation. We observed that the infection with HRV16 replicated key hallmarks of the cytopathology and inflammatory responses observed in human airways. Generation of a T-helper cell type 2 microenvironment through exogenous IL-13 stimulation induced features of asthmatic airways, including goblet cell hyperplasia, reduction of cilia beating frequency, and endothelial activation, but did not alter rhinovirus infectivity or replication. High-resolution kinetic analysis of secreted inflammatory markers revealed that IL-13 treatment altered IL-6, IFN-λ1, and CXCL10 secretion in response to HRV16. Neutrophil transepithelial migration was greatest when viral infection was combined with IL-13 treatment, whereas treatment with MK-7123, a CXCR2 antagonist, reduced neutrophil diapedesis in all conditions. In conclusion, our microengineered Airway Lung-Chip provides a novel human-relevant platform for exploring the complex mechanisms underlying viral-induced asthma exacerbation. Our data suggest that IL-13 may impair the hosts’ ability to mount an appropriate and coordinated immune response to rhinovirus infection. We also show that the Airway Lung-Chip can be used to assess the efficacy of modulators of the immune response.

病毒引起的哮喘恶化仍然是住院和死亡的主要原因。迫切需要新的与人相关的呼吸道模型，以了解呼吸道感染如何触发哮喘发作并促进治疗的发展。在这里，我们描述了一种新的与人类有关的鼻病毒诱发的哮喘加重模型，该模型概括了哮喘气道上皮和中性粒细胞跨上皮迁移的病毒感染，并能够评估免疫调节疗法。具体而言，用IL-13刺激完全分化的人类粘膜纤毛上皮微结构模型，以诱导T型辅助细胞2型哮喘表型，并感染活的人类鼻病毒16（HRV16），以重现病毒性哮喘加重的关键特征。我们观察到，HRV16感染复制了在人气道中观察到的细胞病理学和炎症反应的关键标志。通过外源性IL-13刺激产生的2型T辅助细胞微环境诱导了哮喘气道的特征，包括杯状细胞增生，纤毛跳动频率降低和内皮活化，但并未改变鼻病毒的感染性或复制。分泌的炎症标记物的高分辨率动力学分析表明，IL-13治疗可响应HRV16改变IL-6，IFN-λ1和CXCL10的分泌。当病毒感染与IL-13治疗联合使用时，嗜中性白血球的上皮迁移最大，而CXCR2拮抗剂MK-7123的治疗在所有情况下均减少了嗜中性白血球的尿布。结论，我们的微工程化气道肺芯片为探索病毒性哮喘加重的复杂机制提供了一个与人相关的新颖平台。我们的数据表明，IL-13可能削弱宿主针对鼻病毒感染进行适当且协调的免疫反应的能力。我们还表明，气道肺芯片可用于评估免疫应答调节剂的功效。