The role of sex in the evolution and spread of virulent infectious disease

所有生物体都受到病原体的困扰，wiiicfi可以迅速进化以克服iiost防御，导致 增加宿主损害或死亡率（毒力）。宿主的遗传变异性提供了一种防御手段 致命的潜力。一种鼠逆转录病毒的实验进化揭示了适应性增加了156倍， 在通过单基因型宿主仅仅10次连续传代后，毒力增加了10倍，但这些显著的 当病毒面对五种交替的宿主基因型时，增加被完全消除。的条件 促进高传播也预测有利于高毒力。例如，马立克氏病的毒力 在过去的几十年里，鸡的疾病病毒作为传播的障碍一直在稳步增加， 宿主遗传多样性已经减少。本研究的长期目标是确定机制 控制病原体的毒力进化，这将导致控制疾病的方法 从这样的毒力增加。这项研究操纵了传播水平和宿主遗传水平， 在实验病毒进化过程中的多样性，以量化每个因素如何控制病原体的进化 传播、复制和毒力（目标1）。这些实验将在两个宿主-小鼠-中进行。 (Mus)和鸡（Gallus），代表模式哺乳动物和禽类农业物种。为每个 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，以确定病毒的遗传基础， 传播性，复制和毒力变化（目标2），这将推动未来的实验，以发现 具体机制。这些经验数据将构成数学模型发展的基础 需要从病原体复制和毒力进化推断宿主后果（目标3）。的能力 通过实验和真实的时间来研究这些过程，提供了一种强有力但未充分利用的工具， 剖析宿主和病原体之间复杂的相互作用，这对于理解 和控制病原体引起的疾病。 相关性（参见说明）： 除了传染病本身，病原体还引起其他疾病，如癌症，自身免疫和逃逸 疫苗免疫。这项研究确定了病原体毒力演变的原因， （1）控制病原体引起的疾病，（2）控制新的传染病的出现，（3） 准备对付使用病原体作为生物恐怖主义武器，4）控制全球抗生素- 通过减少家养动物对口服抗生素的需求来减少耐药性危机

Ail organisms are plagued by pathiogens, wiiicfi can rapidly evolve to overcome iiost 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 ofthe 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 powerfulyet under-utilized tool for dissecting the complex interactions between hosts and pathogens, which will be important for understanding and controlling pathogen-caused diseases. RELEVANCE (See instructions): Beyond infectious disease itself, pathogens cause other diseases such as cancer, autoimmunity, and escape from vaccine immunity. This study identifies the causes of evolving pathogen virulence, which is fundamental to: 1) controlling pathogen-caused diseases, 2) controlling the emergence of new infectious diseases, 3) preparing against the use of pathogens as bioterrorism weapons and 4) controlling the global, antibiotic- resistance crisis bv minimizing the need for orophvlactic antibiotics in domestir animals