Effects of obesity on the dynamics of Influenza transmission

总体摘要 我们和其他人已经证明，肥胖是发展成严重流感感染的一个独立风险因素。 然而，其影响超出了疾病的严重性。病毒清除受到影响，导致病毒持续时间延长 正在脱落。疫苗效力降低，最近的一项研究表明，超重/肥胖的成年人 流感病毒比人的平均体重长102%。使用我们新开发的饮食诱导肥胖 (Dio)雪貂模型我们现在表明肥胖影响流感传播。一种禽流感H9N2病毒， 不会通过空气中的飞沫在瘦雪貂身上传播，在100%的肥胖动物中传播。这些 考虑到世界卫生组织(WHO)预测大多数 的世界人口生活在超重和肥胖比肥胖更普遍的国家 体重过轻。 我们的总体目标是确定肥胖如何影响流感病毒的传播。我们将决定 传播的增强是由于病毒的变化，还是由于肥胖宿主的易感性增加，或者 到两者的组合，回答关于病毒在肥胖宿主中是否以不同方式进化的问题 与瘦弱的主人相比。最后，我们将探讨接种疫苗是否能保护苗条和肥胖的宿主。我们 假设免疫功能降低的肥胖宿主可能是病毒的宿主， 使它们能够有效地适应新的宿主，并形成潜在更容易的遗传变异 已发送。我们提议的研究将填补知识的空白，这是旨在 了解传播中涉及的宿主因素以及疫苗接种在阻止这些事件中的作用。 为了实现我们的目标，我们提出了以下三个相互关联但独立的具体目标 这将解决主机与病毒的交互问题： 1.确定病毒多样性并量化传播动态。 2.探讨疫苗在肥胖宿主中的保护作用及其对传播的影响。 3.确定肥胖宿主对流感感染的易感性。 鉴于我们在流感进化方面的综合专业知识，我们非常适合从事这项工作 通过深度测序的传播动力学，以及肥胖对流感疾病严重程度和疫苗的影响 回应。除了肥胖的雪貂模型，我们还开发了创新的工具来定义宿主 雪貂的反应对许多调查人员来说将是无价的。最后，我们可以进入纵向鼻腔 与相应的体重指数(BMI)数据一起从感染流感的人群中洗涤，使我们能够 开始将我们的发现转化为人类健康。从长远来看，这些研究可能会揭示出关键的新 关于肥胖对流感感染、传播和疫苗保护的公共健康影响的信息。 可能会延伸到流感以外的信息。

OVERALL ABSTRACT We, and others have shown that obesity is an independent risk factor for developing severe influenza infection. However, the impact goes beyond disease severity. Viral clearance is impacted leading to prolonged viral shedding. Vaccine efficacy is reduced and a recent study showed that overweight/obese adults shed influenza virus 102% longer than average weight people. Using our newly developed diet-induced obese (DIO) ferret model we now show that obesity impacts influenza transmission. An avian H9N2 virus that does not transmit via airborne droplets in lean ferrets transmits in 100% of obese animals tested. These findings have dramatic ramifications considering that the World Health Organization (WHO) predicts that most of the world’s population lives in countries where being overweight and obese is more prevalent than being underweight. Our overall goal is to determine how obesity impacts influenza virus transmission. We will determine whether enhanced transmission is due to changes in the virus, to increased susceptibility of the obese host, or to a combination of both, answering questions on whether the virus evolves differently in the obese host as compared to the lean host. Finally, we will explore whether vaccination protects lean and obese hosts. We hypothesize that obese hosts, who have reduced immune function, may be acting as reservoirs for viruses, allowing them to efficiently adapt to the new host and form genetic variants that can potentially be more easily transmitted. Our proposed studies will fill a gap in knowledge by being the first work aimed at also understanding host factors involved in transmission and the role of vaccination in stopping these events. To accomplish our goal, we have proposed the following three interconnected but independent specific aims that will address host-virus interactions: 1. Characterize virus diversity and quantify the dynamics of transmission. 2. Explore vaccine-based protection in the obese host and its effect on transmission. 3. Determine host susceptibility to influenza infection in the obese host. We are uniquely suited to undertake this work given our combined expertise in influenza evolution and transmission dynamics by deep sequencing, and impact of obesity on influenza disease severity and vaccine responses. In addition to the obese ferret model, we have developed innovative tools to define the host response in ferrets that will be invaluable to many investigators. Finally, we have access to longitudinal nasal washes from influenza-infected human cohorts with corresponding body-mass index (BMI) data allowing us to begin translating our findings to human health. In the long term, these studies may reveal critical new information on the public health impact of obesity on influenza infection, transmission, and vaccine protection. Information that is likely to extend beyond influenza.