Admin Supplement - Effects of obesity on the dynamics of Influenza transmission

管理补充 - 肥胖对流感传播动态的影响

• 批准号: 10171538
• 负责人: David Gresham
• 金额: $ 16.01万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171538
• 关键词: Address; Affect; Animal Testing; Animals; Avian Influenza; Birds; Body mass index; Cells; China; Country; Data; Diet; Disease; Dose; Epidemic; Event; Evolution; Exhalation; Expression Profiling; Family suidae; Ferrets; Gene Expression; Goals; Health; Human; Immune response; Individual; Infection; Influenza; Influenza A Virus, H7N9 Subtype; Influenza A Virus, H9N2 Subtype; Innate Immune Response; Integration Host Factors; Knowledge; Longitudinal Studies; Modeling; Molecular; Morbidity - disease rate; Mutation; Non obese; Nose; Obese Mice; Obesity; Overweight; Patients; Population; Populations at Risk; Predisposition; Public Health; RNA Viruses; Reporting; Research Personnel; Risk Factors; Role; Sampling; Severity of illness; Structure; Testing; Thinness; Time; Translating; Underweight; Vaccinated; Vaccination; Vaccines; Viral; Viral Respiratory Tract Infection; Viral reservoir; Virus; Virus Shedding; Weight; Work; World Health Organization; adult obesity; base; cohort; deep sequencing; epidemiologic data; flu transmission; genetic variant; high risk; immune function; influenza epidemic; influenzavirus; innovation; mortality; novel; pressure; response; tool; transmission process; vaccine effectiveness; vaccine efficacy; vaccine response; viral transmission; virus host interaction

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.

总体摘要 我们和其他人已经证明，肥胖是发生严重流感感染的独立危险因素。 然而，其影响超出了疾病的严重程度。病毒清除受到影响，导致病毒持续时间延长。 疫苗效力降低，最近的一项研究表明，超重/肥胖的成年人会脱落。 流感病毒比平均体重的人长102% 使用我们新开发的饮食诱发肥胖。 (DIO) 雪貂模型，我们现在表明肥胖会影响流感传播的禽类 H9N2 病毒。 瘦雪貂中不会通过空气中的飞沫传播，在测试的肥胖动物中 100% 会传播。 考虑到世界卫生组织 (WHO) 预测大多数人 的世界人口生活在超重和肥胖比肥胖更普遍的国家 体重不足。 我们的总体目标是确定肥胖如何影响流感病毒的传播。 传播增强是否是由于病毒的变化、肥胖宿主的易感性增加，或者 结合两者，回答病毒在肥胖宿主中是否以不同方式进化的问题 最后，我们将探讨疫苗接种是否可以保护瘦人和肥胖的宿主。 免疫功能下降的肥胖宿主可能成为病毒的储存库， 使它们能够有效地适应新宿主并形成可能更容易发生的遗传变异 我们提出的研究将作为第一个旨在填补知识空白的工作。 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 这将解决宿主与病毒的相互作用： 1. 表征病毒多样性并量化传播动态。 2. 探索基于疫苗的肥胖宿主保护及其对传播的影响。 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和 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 除了肥胖雪貂模型之外，我们还开发了创新工具来定义宿主。 雪貂的反应对于许多研究人员来说都是无价的 最后，我们可以获得纵向鼻腔。 从感染流感的人群中洗出的样本以及相应的体重指数 (BMI) 数据使我们能够 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重要的新内容。 有关肥胖对流感感染、传播和疫苗保护的公共卫生影响的信息。 可能超出流感范围的信息。