Evolution and Transmission of Influenza Virus in Natural Human Infection

季节性流感流行导致显著的发病率和死亡率，疫苗的有效性受到影响。 令人沮丧的低。流感病毒的快速进化是有效疫苗的主要障碍， 具有不同抗原特性的菌株在相当大的群体中连续产生， 感染的宿主最近NIAID的流感战略计划和PA-18-859强调了这一问题， 其中强调了有关流感病毒在个体中演变及其传播的关键知识差距 他们之间这项研究的长期目标是阐明进化和流行病学动态 流感病毒在自然感染的人类宿主中的作用。该项目的目标是使用最先进的 分子方法来定义流感的宿主水平演变，并确定传染性的相关性， 传输该项目将联合收割机结合病毒、匹配血清和临床数据的密集采样， 自然感染的个体及其接触者，这将允许对流感演变进行强有力的分析， 传播和扩散。这种方法的可行性得到了已公布的初步数据的支持，这些数据表明， （i）连续采样可用于表征自然界中流感病毒的进化动力学， 感染者;（ii）下一代测序（NGS）可用于识别传播对并估计 个体之间传播的独特病毒变体的数量;（iii）关于病毒载量的时间数据，以及- 宿主遗传多样性可以为传播的数学模型提供信息。流感演变的详细分析 并且传输将在三个目标中完成。(Aim 1）识别出现的抗原变体， 积极选择与主机。将使用连续采样的宿主内病毒群体的NGS来鉴定 正选择作用下的血凝素和神经氨酸酶变异体及其与宿主的关系 免疫状态这些突变对病毒抗原性的影响将使用来自入组的受试者的血清进行评价。 个体(Aim 2）定义传播瓶颈和被传播的遗传变异。NGS 将使用索引病例和家庭接触者的系列样本来确定家庭传播链， 传输瓶颈的大小，以及在主机变量中传输哪些变量。(Aim 3）识别病毒和 与宿主易感性、传染性和传播相关的宿主因素。一个特定的家庭 一个整合了分子学和流行病学数据的传播模型将被用来估计感染的危害 从社区和每个受感染的家庭接触。这项工作是创新的，因为它利用了 现有生产团队的专业知识，将最先进的病毒测序技术与联合收割机结合起来， 先进的建模方法，研究流感病毒的进化和自然感染的传播。的 拟议中的研究是重要的，因为它将定义流感病毒的进化动力学水平， of individual个人hosts主机in a community社区setting设置.

Seasonal influenza epidemics result in significant morbidity and mortality, and vaccine effectiveness is disappointingly low. The rapid evolution of influenza viruses is a major barrier to effective vaccines, as new strains with different antigenic properties are continuously generated within a remarkably large population of infected hosts. This problem was highlighted in the recent NIAID strategic plan for influenza and in PA-18-859, which highlight key knowledge gaps with respect to influenza virus evolution in individuals and its transmission between them. The long-term goal of this research is to elucidate the evolutionary and epidemiological dynamics of influenza viruses in naturally infected human hosts. The objectives of this project are to use state-of-the-art molecular approaches to define the host-level evolution of influenza and to identify correlates of infectivity and transmission. This project will combine intensive sampling of viruses, matched sera, and clinical data from naturally infected individuals and their contacts, which will allow for robust analyses of influenza evolution, transmission, and spread. The feasibility of this approach is supported by published preliminary data, which show that (i) serial sampling can be used to characterize the evolutionary dynamics of influenza viruses within naturally infected people; (ii) next generation sequencing (NGS) can be used to identify transmission pairs and to estimate the number of unique viral variants transmitted between individuals; (iii) temporal data on viral load and within- host genetic diversity can inform mathematical models of transmission. Detailed analyses of influenza evolution and transmission will be accomplished in three aims. (Aim 1) Identify the emergent antigenic variants that are positively selected with hosts. NGS of serially sampled within-host viral populations will be used to identify hemagglutinin and neuraminidase variants under positive selection within hosts and their relationship to host immune status. The impact of these mutations on viral antigenicity will be evaluated using sera from enrolled individuals. (Aim 2) Define the transmission bottleneck and the genetic variants that are transmitted. NGS of serial samples from index cases and household contacts will be used to define household transmission chains, the size of the transmission bottleneck, and which within host variants are transmitted. (Aim 3) Identify viral and host factors associated with host susceptibility, infectivity, and transmission. A strain-specific household transmission model, integrating molecular and epidemiologic data, will be used to estimate hazards of infection from the community and each infected household contact. This work is innovative, because it leverages the expertise of an existing productive team to combine state-of-the-art technologies for viral sequencing and sophisticated modeling approaches to study influenza virus evolution and transmission in natural infection. The proposed research is significant, because it will define the evolutionary dynamics of influenza viruses at the level of individual hosts in a community setting.