Department of Pathology, University of New South Wales, Sydney, NSW, Australia.
Respir Res. 2010 Feb 3;11(1):14. doi: 10.1186/1465-9921-11-14.
Early-life respiratory viral infections, notably with respiratory syncytial virus (RSV), increase the risk of subsequent development of childhood asthma. The purpose of this study was to assess whether early-life infection with a species-specific model of RSV and subsequent allergen exposure predisposed to the development of features of asthma.
We employed a unique combination of animal models in which BALB/c mice were neonatally infected with pneumonia virus of mice (PVM, which replicates severe RSV disease in human infants) and following recovery, were intranasally sensitised with ovalbumin. Animals received low-level challenge with aerosolised antigen for 4 weeks to elicit changes of chronic asthma, followed by a single moderate-level challenge to induce an exacerbation of inflammation. We then assessed airway inflammation, epithelial changes characteristic of remodelling, airway hyperresponsiveness (AHR) and host immunological responses.
Allergic airway inflammation, including recruitment of eosinophils, was prominent only in animals that had recovered from neonatal infection with PVM and then been sensitised and chronically challenged with antigen. Furthermore, only these mice exhibited an augmented Th2-biased immune response, including elevated serum levels of anti-ovalbumin IgE and IgG1 as well as increased relative expression of Th2-associated cytokines IL-4, IL-5 and IL-13. By comparison, development of AHR and mucous cell change were associated with recovery from PVM infection, regardless of subsequent allergen challenge. Increased expression of IL-25, which could contribute to induction of a Th2 response, was demonstrable in the lung following PVM infection. Signalling via the IL-4 receptor alpha chain was crucial to the development of allergic inflammation, mucous cell change and AHR, because all of these were absent in receptor-deficient mice. In contrast, changes of remodelling were evident in mice that received chronic allergen challenge, regardless of neonatal PVM infection, and were not dependent on signalling via the IL-4 receptor.
In this mouse model, interaction between early-life viral infection and allergen sensitisation/challenge is essential for development of the characteristic features of childhood asthma, including allergic inflammation and a Th2-biased immune response.
婴儿期呼吸道病毒感染，特别是呼吸道合胞病毒（RSV）感染，会增加随后发生儿童哮喘的风险。本研究的目的是评估婴儿期感染呼吸道合胞病毒的特定物种模型以及随后的过敏原暴露是否会导致哮喘特征的发展。
我们采用了一种独特的动物模型组合，其中 BALB/c 小鼠在新生儿期感染鼠肺炎病毒（PVM，该病毒在人类婴儿中复制严重的 RSV 疾病），并在恢复后用卵清蛋白进行鼻内致敏。动物接受低水平的雾化抗原 4 周以引发慢性哮喘变化，然后进行单次中度水平的挑战以引发炎症加重。然后，我们评估了气道炎症、重塑特征的上皮变化、气道高反应性（AHR）和宿主免疫反应。
只有从 PVM 新生儿感染中恢复过来，然后用抗原进行致敏和慢性挑战的动物才会出现明显的过敏性气道炎症，包括嗜酸性粒细胞的募集。此外，只有这些小鼠表现出增强的 Th2 偏向免疫反应，包括血清中抗卵清蛋白 IgE 和 IgG1 水平升高以及 Th2 相关细胞因子 IL-4、IL-5 和 IL-13 的相对表达增加。相比之下，AHR 和粘液细胞变化的发展与 PVM 感染的恢复有关，而与随后的过敏原挑战无关。在 PVM 感染后，可检测到 IL-25 的表达增加，这可能有助于诱导 Th2 反应。IL-4 受体 alpha 链的信号传导对于过敏性炎症、粘液细胞变化和 AHR 的发展至关重要，因为这些在受体缺陷型小鼠中均不存在。相比之下，慢性过敏原挑战后，无论新生儿 PVM 感染与否，都可以观察到重塑变化，并且不依赖于 IL-4 受体的信号传导。
在这种小鼠模型中，婴儿期病毒感染和过敏原致敏/挑战之间的相互作用对于发展儿童哮喘的特征，包括过敏性炎症和 Th2 偏向免疫反应是必不可少的。
