The evolution and spread of virulent infectious disease

描述（由申请人提供）：所有生物体都受到病原体的困扰，病原体可以迅速进化以克服宿主防御，导致宿主损害或死亡率（毒力）增加。宿主的遗传变异性提供了一种防御这种致命潜力的方法。小鼠逆转录病毒的实验进化表明，在单基因型宿主中连续传代 10 次后，适应性增加了 156 倍，毒力增加了 11 倍，但当病毒面对 5 个交替的宿主基因型时，这些显着的增加就完全消失了。预计促进高传播的条件也有利于高毒力。例如，随着传播障碍和宿主遗传多样性的减少，鸡马立克氏病病毒的毒力在过去几十年中一直在稳步增加。这项研究的长期目标是确定控制毒力进化的机制 病原体，这将导致控制由这种毒力增加而出现的疾病的方法。这项研究在实验病毒进化过程中操纵传播和宿主遗传多样性的水平，以量化每个因素如何控制病毒的进化。 病原体的传播性、复制性和毒力（目标 1）。这些实验将在两种宿主中进行：小鼠（Mus）和鸡（Gallus），分别代表模型哺乳动物和鸟类农业物种。对于每个宿主，将独立评估两种不同的病毒病原体。我们将利用深度测序技术来询问进化病毒的整个基因组，以确定病毒传播性、复制性和毒力变化的遗传基础（目标2），这将为未来发现特定机制的实验提供动力。这些经验数据将构成开发数学模型的基础，以推断病原体复制和毒力进化对宿主的影响（目标 3）。通过实验和实时研究这些过程的能力为剖析宿主和病原体之间复杂的相互作用提供了一个强大但未充分利用的工具，这对于理解和控制病原体引起的疾病非常重要。

DESCRIPTION (provided by applicant): All organisms are plagued by pathogens, which can rapidly evolve to overcome host defenses, resulting in increased host damage or mortality (virulence). Genetic variability of hosts provides one defense against this deadly potential. Experimental evolution of a murine retrovirus revealed 156-fold increases in fitness and 11-fold increases in virulence after just 10 serial passages through single-genotype hosts, but these dramatic increases were completely abolished when the virus faced five alternating host genotypes. Conditions that promote high transmission are also predicted to favor high virulence. For example, the virulence of Marek's disease virus of chickens has been steadily increasing over the past decades as barriers to transmission and host genetic diversity have been reduced. The long term objective of this study is to identify the mechanisms controlling virulence evolution of pathogens, which will lead to approaches for controlling the diseases emerging from such virulence increases. This study manipulates levels of both transmission and host genetic diversity during experimental viral evolution to quantify how each factor controls the evolution of pathogen transmissibility, replication and virulence (Aim 1). These experiments will be conducted in two hosts - mice (Mus) and chickens (Gallus), representing a model mammal and an avian agricultural species. For each host, two separate viral pathogens will be independently evaluated. We will utilize deep sequencing techniques to interrogate the entire genomes of the evolved viruses to identify the genetic basis of viral transmissibility, replication and virulence changes (Aim 2), which will fuel future experiments to discover specific mechanisms. These empirical data will form a basis for the development of mathematical models needed to deduce host consequences from pathogen replication and virulence evolution (Aim 3). The ability to study these processes experimentally and in real time provides a powerful yet under-utilized tool for dissecting the complex interactions between hosts and pathogens, which will be important for understanding and controlling pathogen-caused diseases.