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，导致宿主损伤或死亡率增加（毒力）。宿主的遗传变异性提供了一种防御这种致命潜力的方法。鼠逆转录病毒的实验进化显示，通过单一基因型宿主连续传代10次后，适应性增加了156倍，毒力增加了11倍，但当病毒面临5种交替宿主基因型时，这些急剧增加被完全消除。促进高传播的条件也被预测有利于高毒力。例如，鸡马立克氏病病毒的毒力在过去几十年中随着传播障碍和宿主遗传多样性的减少而稳步增加。本研究的长期目标是确定控制毒力进化的机制 这将导致控制因这种毒力增加而出现的疾病的方法。这项研究在实验性病毒进化过程中操纵了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、复制和毒力（目标1）。这些实验将在两种宿主-小鼠（Mus）和鸡（Gallus）中进行，代表模型哺乳动物和禽类农业物种。对于每种宿主，将独立评价两种单独的病毒病原体。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，复制和毒力变化的遗传基础（目标2），这将为未来的实验提供动力，以发现特定的机制。这些经验数据将形成一个基础的数学模型的发展需要推断主机的后果从病原体复制和毒力进化（目标3）。通过实验和真实的时间研究这些过程的能力为剖析宿主和病原体之间的复杂相互作用提供了一个强大但未得到充分利用的工具，这对于理解和控制病原体引起的疾病将是重要的。

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.