MECHANISMS REGULATING AVIAN INFLUENZA VIRUS INFECTIONS IN HUMANS

摘要 禽流感病毒（AIV）与更严重的疾病有关，但感染后的传播性较低 比季节性流感病毒更严重。动物模型和单个或小簇的有限研究 AIV人类病例已被用于了解潜在的机制，并取得了不同的成功， 推论在很大程度上阻碍科学进步的是历史上的零星性质， 人类AIV病例，使得比较和广泛的前瞻性研究不可行。的出现 H7N9禽流感在中国的爆发改变了这一点。这些H7N9病例与可预测的空间和 时间模式，使其可行的考虑队列研究。在这里，我们建议进行纵向 这项研究旨在确定人类AIV感染的免疫学和病毒学标志。我们的研究 将检验两个假设：1）H7N9 AIV引起的严重疾病是缺乏早期交叉的结果， 保护性CD8+ T细胞应答，以及2）AIV在哺乳动物宿主中的复制限制了病毒群体 这反过来又限制了向前传输。中国南方是一个特别重要的地区， 由于人和家禽的高密度，禽流感病例。我们建议的研究地点在第一次 广州医科大学附属医院，也是指定的国家参考中心， 呼吸系统疾病，非常适合这项研究。上述目标的完成将导致最 迄今为止，对人类AIV感染的全面分析，以及与 季节性流感美国和中国科学家的关键交叉培训也将是一个重要的里程碑， 提高全球公共卫生研究能力。

ABSTRACT Avian influenza viruses (AIVs) are associated with more severe disease but less transmissibility after infection of humans than are seasonal influenza viruses. Animal models and limited studies of single or small clusters of AIV human cases have been utilized to understand the underlying mechanisms with varying success and inference. Hampering scientific progress to a substantial degree has been the historically sporadic nature of human AIV cases, making comparative and extensive prospective studies unfeasible. The emergence of the H7N9 AIV in China has now changed this. These H7N9 cases are associated with a predictable spatial and temporal pattern that makes it feasible to consider a cohort study. Here, we propose to conduct a longitudinal study to identify the immunological and virological hallmarks of AIV infections in humans. Our study will test two hypotheses: 1) severe disease caused by H7N9 AIVs is a consequence of a lack of early cross- protective CD8+ T-cell responses, and, 2) replication of AIVs in the mammalian host limits virus population diversity which in turn limits onwards transmission. Southern China is a particularly important region for human cases of AIV due to its high density of humans and domestic poultry. Our proposed study site at the First Affiliated Hospital of Guangzhou Medical University, which is also a designated National Reference Center for Respiratory Diseases, is perfectly suited for this study. The completion of the above aims will lead to the most comprehensive analysis of AIV infections in humans to date and also to a direct side-by-side comparison with seasonal influenza. Critical cross training of US and Chinese scientists will also be a major milestone leading to improved global public health research capacity.