Biology of Influenza Virus Transmission

流感病毒传播的生物学

• 批准号: 10413155
• 负责人: Mila Brum Ortigoza
• 金额: $ 18.64万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-08 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413155
• 关键词: Address; Adult; Affect; Age; Animal Model; Antiviral Therapy; Biology; Cavia; Characteristics; Data; Environment; Event; Experimental Models; Ferrets; Financial Hardship; Future; Goals; Hemagglutinin; Human; Humoral Immunities; Immune; Immunity; Immunoglobulins; Infant; Infection; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Integration Host Factors; Interruption; Investigation; Knowledge; Modeling; Modification; Molecular; Mus; Natural Immunity; Neuraminidase; Neuraminidase inhibitor; Pathogenesis; Play; Population; Predisposition; Prevention strategy; Preventive vaccine; Reagent; Research; Role; Sialic Acids; Societies; Streptococcus pneumoniae; Therapeutic; Upper respiratory tract; Vaccination; Vaccine Therapy; Vaccines; Viral; Virion; Virus; Virus Diseases; Virus Shedding; Work; base; burden of illness; contagion; design; flu transmission; guinea pig model; immunological status; in vivo; influenza infection; influenza virus strain; influenza virus vaccine; influenzavirus; insight; mouse model; novel; novel strategies; novel therapeutics; novel vaccines; pandemic disease; prevent; pup; respiratory; trait; transmission process; vaccine effectiveness; viral transmission; virus tropism

PROJECT SUMMARY The long-term goal of this project is to obtain a better understanding of the molecular determinants for influenza A virus (IAV) infectivity and susceptibility in order to devise better strategies for prevention of IAV transmission. Our approach emanates from the existing limitations of our seasonal inactivated influenza virus (IIV) vaccine in which low vaccination coverage and vaccine effectiveness restrict the desired protection from viral acquisition, shedding, and continued transmission. This points to a critical need to devise new strategies to interrupt host-to-host transmission. Our understanding of the host factors contributing to viral contagion is very limited due to the complexities of studying natural transmission in humans and a lack of tractable animal models. Furthermore, most transmission studies in experimental models do not account for host characteristics that could affect IAV transmissibility and susceptibility. Hence, we recently developed an infant mouse model of intra-litter IAV spread that enables elaborate studies of the biology of influenza virus transmission. From this model, we established that high titers of virus shed by the infected donor correlates with the efficiency of transmission, which is dependent on various host factors (such as age and immunity) and viral factors (such as hemagglutinin and neuraminidase). Furthermore, manipulations of the upper respiratory tract (URT) environment (via Streptococcus pneumoniae colonization) revealed that bacterial sialidase expression limited the IAV acquisition by recipients. Together, our preliminary data suggested that the infectivity of IAV relies on the amount of shed virus from the donor to overcome a transmission bottleneck, whereas the susceptibility to IAV relies on the availability of sialic acid in the URT of recipients which may vary, based on the composition of the URT flora. The molecular determinants of virus shedding and sialic acid availability in the URT have not been the focus of previous investigation, vaccine, or therapeutic design. Therefore, in Aim #1, we will evaluate the IAV transmission bottleneck by defining viral and host factors influencing the infectivity (via shedding) of the donor, whereas in Aim #2, we will evaluate the role of sialic acid in the susceptibility to IAV infection through transmission. At the conclusion of the project, we will understand the roles of the host and virus in the infectivity and susceptibility to IAV. We hope to determine whether virus shedding and/or sialic acid availability can be targeted in future studies, as a novel approach to inhibit IAV contagion.

项目摘要 该项目的长期目标是更好地了解分子决定因素的 流感病毒（IAV）感染性和易感性，以制定更好的IAV策略 传播。我们的方法从季节性灭活流感病毒的现有局限性中源 （IIV）低疫苗接种覆盖范围和疫苗有效性限制了所需保护的疫苗 病毒获取，脱落和持续传播。这表明要设计新策略的迫切需要 中断主机到主机传输。 由于复杂性，我们对导致病毒传染的宿主因素的理解非常有限 研究人类的自然传播以及缺乏可拖动的动物模型。此外，大多数 实验模型中的传输研究不考虑可能影响IAV的宿主特征 传递性和敏感性。因此，我们最近开发了一种婴儿小鼠内部IAV扩散模型 这样可以详细研究流感病毒传播的生物学。从这个模型中，我们建立了 受感染供体脱落的高滴度与传播的效率相关，这是 取决于各种宿主因素（例如年龄和免疫力）和病毒因素（例如血凝素和血凝素和病毒因素 神经氨酸酶）。此外，上呼吸道（URT）环境的操纵（通过链球菌 肺炎定殖）表明，细菌唾液酸酶表达限制了受体的IAV获取。 总之，我们的初步数据表明，IAV的感染性取决于来自 克服传输瓶颈的供体，而对IAV的敏感性依赖于唾液的可用性 根据urt植物的组成，受体可能会有所不同的受体中的酸。分子 在URT中，病毒脱落和唾液酸可用性的决定因素并不是以前的重点 研究，疫苗或治疗设计。因此，在AIM＃1中，我们将评估IAV传输 通过定义病毒和宿主因素影响供体的感染性（通过脱落），而在 AIM＃2，我们将评估唾液酸通过传播易感IAV感染的作用。在 该项目的结论，我们将了解宿主和病毒在感染性和易感性中的作用 IAV。我们希望确定病毒脱落和/或唾液酸的可利用率是否可​​以在以后的研究中针对 作为抑制IAV触发的新方法。