Clay Candice C, Reader J Rachel, Gerriets Joan E, Wang Theodore T, Harrod Kevin S, Miller Lisa A
California National Primate Research Center, University of California, Davis, California, USA.
Infectious Disease Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
J Virol. 2014 Jul;88(13):7412-25. doi: 10.1128/JVI.00188-14. Epub 2014 Apr 16.
Influenza is the cause of significant morbidity and mortality in pediatric populations. The contribution of pulmonary host defense mechanisms to viral respiratory infection susceptibility in very young children is poorly understood. As a surrogate to compare mucosal immune responses of infant and adult lungs, rhesus monkey primary airway epithelial cell cultures were infected with pandemic influenza A/H1N1 virus in vitro. Virus replication, cytokine secretion, cell viability, and type I interferon (IFN) pathway PCR array profiles were evaluated for both infant and adult cultures. In comparison with adult cultures, infant cultures showed significantly increased levels of H1N1 replication, reduced alpha interferon (IFN-α) protein synthesis, and no difference in cell death following infection. Age-dependent differences in expression levels of multiple genes associated with the type I IFN pathway were observed in H1N1-infected cultures. To investigate the pulmonary and systemic responses to H1N1 infection in early life, infant monkeys were inoculated with H1N1 by upper airway administration. Animals were monitored for virus and parameters of inflammation over a 14-day period. High H1N1 titers were recovered from airways at day 1, with viral RNA remaining detectable until day 9 postinfection. Despite viral clearance, bronchiolitis and alveolitis persisted at day 14 postinfection; histopathological analysis revealed alveolar septal thickening and intermittent type II pneumocyte hyperplasia. Our overall findings are consistent with the known susceptibility of pediatric populations to respiratory virus infection and suggest that intrinsic developmental differences in airway epithelial cell immune function may contribute to the limited efficacy of host defense during early childhood.
To the best of our knowledge, this study represents the first report of intrinsic developmental differences in infant airway epithelial cells that may contribute to the increased susceptibility of the host to respiratory virus infections. Despite the global burden of influenza, there are currently no vaccine formulations approved for children <6 months of age. Given the challenges of conducting experimental studies involving pediatric patients, rhesus monkeys are an ideal laboratory animal model to investigate the maturation of pulmonary mucosal immune mechanisms during early life because they are most similar to those of humans with regard to postnatal maturation of the lung structure and the immune system. Thus, our findings are highly relevant to translational medicine, and these data may ultimately lead to novel approaches that enhance airway immunity in very young children.
流感是导致儿童群体出现严重发病和死亡的原因。人们对肺部宿主防御机制在幼儿病毒性呼吸道感染易感性方面的作用了解甚少。作为比较婴儿和成人肺部黏膜免疫反应的替代方法，恒河猴原代气道上皮细胞培养物在体外被甲型H1N1大流行性流感病毒感染。对婴儿和成人培养物的病毒复制、细胞因子分泌、细胞活力以及I型干扰素（IFN）途径PCR阵列图谱进行了评估。与成人培养物相比，婴儿培养物显示H1N1复制水平显著增加，α干扰素（IFN-α）蛋白合成减少，且感染后细胞死亡无差异。在感染H1N1的培养物中观察到与I型IFN途径相关的多个基因表达水平存在年龄依赖性差异。为了研究生命早期对H1N1感染的肺部和全身反应，通过上呼吸道给药对幼猴接种H1N1。在14天的时间内对动物的病毒和炎症参数进行监测。在第1天从气道中回收了高滴度的H1N1，病毒RNA在感染后第9天仍可检测到。尽管病毒已清除，但在感染后第14天细支气管炎和肺泡炎仍然存在；组织病理学分析显示肺泡间隔增厚和间歇性II型肺细胞增生。我们的总体研究结果与儿童群体对呼吸道病毒感染的已知易感性一致，并表明气道上皮细胞免疫功能的内在发育差异可能导致幼儿期宿主防御功效有限。
据我们所知，本研究首次报道了婴儿气道上皮细胞的内在发育差异，这可能导致宿主对呼吸道病毒感染的易感性增加。尽管流感具有全球负担，但目前尚无批准用于6个月以下儿童的疫苗制剂。鉴于进行涉及儿科患者的实验研究面临挑战，恒河猴是研究生命早期肺部黏膜免疫机制成熟的理想实验动物模型，因为它们在肺结构和免疫系统的出生后成熟方面与人类最为相似。因此，我们的研究结果与转化医学高度相关，这些数据最终可能导致增强幼儿气道免疫力的新方法。
