The evolution and spread of virulent infectious disease

描述（由申请人提供）：所有生物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）。宿主的遗传变异提供了一种防御这种致命的可能性。小鼠逆转录病毒的实验进化表明，仅在单基因型宿主中连续传代10次后，适应度增加了156倍，毒力增加了11倍，但当病毒面对5个交替的基因型宿主时，这些显著的增加完全消失了。预计促进高传播的条件也有利于高毒力。例如，鸡的马立克病病毒的毒力在过去几十年中一直在稳步增加，因为传播障碍和宿主遗传多样性已经减少。这项研究的长期目标是确定控制毒力进化的机制

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.