Synthesizing the Evolutionary and Ecological Dynamics of Acute RNA Viruses: Compa

综合急性 RNA 病毒的进化和生态动力学：Compa

• 批准号: 7769498
• 负责人: Bryan Grenfell
• 金额: $ 25.84万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-05 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769498
• 关键词: Accounting; Acute; Affect; Age; Beds; Birth; Buffers; Case Study; Communicable Diseases; Computer Simulation; Data; Disease; Ecology; Epidemic; Epidemiology; Evolution; Force of Gravity; Generations; Genes; Genetic Variation; Goals; Herd Immunity; Human; Immune; Immune system; Immunity; Incidence; Infection; Influenza; Link; Measles; Measles virus; Membrane Proteins; Methods; Modeling; Mutation; Parainfluenza; Phylogenetic Analysis; Physiologic pulse; Population; Population Dynamics; Population Growth; Population Sizes; Process; RNA Viruses; Research; Respiratory syncytial virus; Rotavirus; Serotyping; Statistical Models; Structure; Testing; Violence; Viral; Viral Genes; Virus; Work; anthropogenesis; base; combat; comparative; human disease; influenzavirus; insight; life history; novel strategies; pathogen; pressure; simulation; tool; transmission process

DESCRIPTION (provided by applicant): Directly-transmitted acute RNA viruses (ARVs) - such as the influenza A and measles viruses - cause many important human diseases. ARVs typically generate violent epidemics which are terminated by the build up of herd immunity, as hosts' immune systems acquire the ability to combat reinfection. Herd immunity can impose enormous selection pressure on ARVs for immune escape, working on the extensive genetic variation generated by high mutation rates and large population sizes. The evolutionary effects of this selection can be clearly seen in influenza virus, where mutation and selection of viral surface protein genes enables the virus to re-infect hosts, subverting herd immunity. Measles lies at the other end of the evolutionary spectrum: with little immune-driven adaptive evolution and near-perfect herd immunity. Understanding the comparative dynamics and control of ARVs therefore depends on characterizing the interaction between epidemiological and evolutionary processes. However, there is currently no quantitative framework linking data on spatio-temporal disease incidence with epidemiological dynamics and phylogenetic analyses of viral evolutionary dynamics. The goal of the proposed research is to develop and apply such a framework, in a nonstationary world of anthropogenic change. We shall approach this synthesis at both viral gene sequence level and the group level of viral subtypes and serotypes. The specific objectives and methods of this work are: 1. Epidemiological dynamics and sequence evolution of ARVs. To develop and analyze computational models that superimpose both neutral viral evolution and immune escape on the current generation of stochastic gravity models for spatio-temporal transmission dynamics of ARVs. Using this simulation framework as a test-bed, we shall refine current coalescent methods to explicitly estimate the parameters of population growth and decline in ARVs and to properly account for spatial subdivision. 2. Group level strain dynamics of ARVs and the impact of anthropogenic change. To explore a new approach to the interaction between viral immune escape and the impact of anthropogenic/demographic change based on the concept of demographic buffering of environmental fluctuations by loss of immunity. We shall develop models to explore how buffering of birth pulses and anthropogenic change operates in age- and spatially-structured host populations across the observed range of ARV life histories. 3. Case studies. To combine models and phylogenetic methods with disease incidence and viral gene sequence data to explore key issues in the epidemiology, evolution and control of five contrasting and important ARV infections of humans: measles, influenza, rotavirus, respiratory syncytial virus and parainfluenza. The synthesis of population dynamic and evolutionary processes is a key problem in infectious disease ecology. With their potential for rapid evolution, RNA viruses present a major opportunity for exploring how epidemic dynamics drive pathogen evolution, and vice versa, and how both are affected by anthropogenic change. The study will provide new insights into RNA virus evolution, clarify key evolutionary and epidemiological issues, and develop generally applicable statistical and modeling tools.

描述(申请人提供)：直接传播的急性核糖核酸病毒(ARV)--如甲型流感病毒和麻疹病毒--会导致许多重要的人类疾病。抗逆转录病毒通常会产生猛烈的流行病，随着宿主的免疫系统获得对抗再感染的能力，这种流行病会随着群体免疫力的增强而终止。群体免疫可以对抗逆转录病毒药物施加巨大的选择压力，以进行免疫逃逸，处理高突变率和大种群规模所产生的广泛遗传变异。这种选择的进化效果在流感病毒中可以清楚地看到，病毒表面蛋白基因的突变和选择使病毒能够再次感染宿主，从而颠覆群体免疫。麻疹处于进化光谱的另一端：几乎没有免疫驱动的适应性进化和近乎完美的群体免疫。因此，了解抗逆转录病毒药物的相对动态和控制取决于描述流行病学和进化过程之间的相互作用。然而，目前还没有将时空疾病发病率数据与流行病学动态和病毒进化动态的系统发育分析联系起来的量化框架。这项拟议的研究的目标是开发和应用这样一个框架，在一个不稳定的人为变化世界中。我们将在病毒基因序列水平和病毒亚型和血清型的群体水平上探讨这种合成。本研究的具体目标和方法是：1.ARV的流行病学动态和序列进化。开发和分析将中性病毒进化和免疫逃逸叠加在当代ARV时空传播动力学随机重力模型上的计算模型。利用这个模拟框架作为试验台，我们将改进现有的合并方法，以明确估计ARV中种群增长和下降的参数，并适当地考虑空间细分。2.抗逆转录病毒病毒的群体水平株系动力学及人为变化的影响。探索一种新的方法来研究病毒免疫逃逸和人为/人口变化的影响之间的相互作用，其基础是通过免疫丧失对环境波动进行人口缓冲的概念。我们将开发模型来探索在观察到的ARV生活史范围内，出生脉搏的缓冲和人为变化如何在年龄和空间结构的宿主种群中发挥作用。3.案例研究。将模型和系统发育方法与疾病发病率和病毒基因序列数据相结合，探讨人类五种不同和重要的ARV感染：麻疹、流感、轮状病毒、呼吸道合胞病毒和副流感的流行病学、进化和控制的关键问题。种群动态和进化过程的综合是传染病生态学中的一个关键问题。RNA病毒具有快速进化的潜力，为探索流行动力学如何驱动病原体进化，反之亦然，以及两者如何受到人为变化的影响提供了重要机会。这项研究将为RNA病毒的进化提供新的见解，澄清关键的进化和流行病学问题，并开发普遍适用的统计和建模工具。