Biology of Influenza Virus Transmission

项目摘要 该项目的长期目标是更好地了解分子决定因素， 流感A病毒（IAV）的感染性和易感性，以便制定更好的预防策略 传输我们的方法源于我们的季节性灭活流感病毒的现有局限性 (IIV)低疫苗接种覆盖率和疫苗有效性限制了所需的保护， 病毒获得、脱落和持续传播。这表明迫切需要制定新的战略， 中断主机到主机传输。 由于病毒感染的复杂性，我们对导致病毒感染的宿主因素的理解非常有限 研究人类的自然传播和缺乏易驾驭的动物模型。而且大多数 实验模型中的传播研究没有考虑可能影响IAV的宿主特征 传染性和易感性。因此，我们最近建立了一个婴儿小鼠模型，在同窝IAV传播 这使得对流感病毒传播的生物学进行详细研究成为可能。根据这个模型，我们建立了 受感染的献血者排出的高滴度病毒与传播效率相关， 取决于各种宿主因素（如年龄和免疫力）和病毒因素（如血凝素和 神经氨酸酶）。此外，上呼吸道（URT）环境的操作（通过链球菌 pneumoniae定植）显示细菌唾液酸酶表达限制了受体获得IAV。 总之，我们的初步数据表明，IAV的传染性取决于从病毒中脱落的病毒量。 供体克服传播瓶颈，而对IAV的易感性依赖于唾液酸的可用性， 受体的URT中的酸，其可以基于URT植物群的组成而变化。分子 URT中病毒脱落和唾液酸可用性的决定因素尚未成为先前研究的焦点。 研究、疫苗或治疗设计。因此，在目标#1中，我们将评估IAV传输 通过定义影响供体感染性（通过脱落）的病毒和宿主因素， 目的#2，我们将评估唾液酸在通过传播感染IAV的易感性中的作用。在 通过该项目的结束，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/或唾液酸可用性是否可以在未来的研究中作为目标， 作为抑制IAV传染的新方法。

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.