Biology of Influenza Virus Transmission

项目总结 这个项目的长期目标是更好地了解分子决定因素 甲型流感病毒(IAV)的传染性和敏感性，以制定更好的预防策略 变速箱。我们的做法源于我们季节性灭活流感病毒的现有局限性。 (Iiv)接种覆盖率低和疫苗效力低的疫苗 病毒的获取、脱落和持续传播。这表明迫切需要制定新的战略来 中断主机到主机的传输。 由于复杂性，我们对导致病毒传播的宿主因素的了解非常有限。 缺乏对人类自然传播的研究，以及缺乏可驯化的动物模型。此外，大多数 实验模型中的传播研究没有考虑到可能影响IAV的宿主特征 传播性和易感性。因此，我们最近开发了一种幼鼠IAV在窝内传播的模型 这使得对流感病毒传播的生物学进行详细研究成为可能。从这个模型出发，我们建立了 受感染的捐赠者排出的高滴度病毒与传播效率有关，这是 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，对上呼吸道(URT)环境的操纵(通过链球菌 肺炎杆菌定植)显示细菌唾液酸酶的表达限制了接受者获得IAV。 总而言之，我们的初步数据表明，IAV的传染性取决于从 供体克服传播瓶颈，而对IAV的敏感性取决于唾液酸的可用性 接受者的城市轨道交通中的酸，根据城市轨道交通菌群的组成，可能会有所不同。分子 在城市轨道交通中，病毒脱落和唾液酸有效性的决定因素并不是以前研究的重点 研究、疫苗或治疗设计。因此，在目标1中，我们将评估IAV的传播 瓶颈通过定义病毒和宿主因素影响捐赠者的传染性(通过脱落)，而在 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 项目结束后，我们将了解宿主和病毒在传染性和易感性中的作用。 IAV.我们希望在未来的研究中确定病毒脱落和/或唾液酸可用性是否可以作为目标， 作为一种抑制IAV传播的新方法。

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.