Evolutionary innovations from host-microbe interactions

项目摘要 微生物及其宿主的基因组随着时间的推移而交织在一起。病原微生物 进化出操纵宿主细胞功能的机制，宿主进化出防御机制， 免受感染在宿主-微生物冲突的进化史中， 编码的创新带来了关键的优势。有时这些功能的发现 提供了一个机会来利用这个过程作为一个研究工具。抗体，限制性 核酸内切酶和CRISPR/Cas系统是天然免疫过程的实例 被重新用于革新现代生物学这项建议的一个核心前提是， 宿主-微生物冲突是生物学创新的熔炉。我们的方法指南 使用互补的计算和实验分析进行严格的多学科研究 研究不同的宿主和微生物过程。我们的工作揭示了一种新的广泛的 发挥抗病毒功能。通过考虑包膜病毒的进化意义 利用运输所需的内体分选复合物（ESCRT）途径，我们 发现了一种新的宿主免疫功能，由retroCHMP 3编码，可以阻止 从受感染的细胞中成熟病毒颗粒。除了描述进化过程之外 为了实现这一特定的生物创新，我们将开发新的计算管道， 发现不同哺乳动物基因组中相关的抗菌功能。工作也 揭示了逆转录转座子和其他自私的遗传元件在创造和 调节与宿主病毒冲突有关的基因。与自私行为有关的新发现 基因也适用于我们对DNA病毒进化的研究。以牛痘病毒为模型系统 对于大型DNA病毒的进化，我们正在进行几个实验方案， 病毒适应机制。一个例子解决了病毒如何获得宿主的问题 基因通过水平转移，这是一种在不同病毒类别中常见的适应机制。 发现反转录转座子在将宿主转录本转移到病毒基因组中的主要作用 将细菌中噬菌体转导的经典工作与真核系统联系起来， 一系列新的问题涉及病毒控制不同物种之间的遗传交换。 最后，我们将把我们的研究扩展到专用免疫防御系统之外的宿主系统， 其中包括一个研究蛋白质调节水的快速进化的有趣信号的项目 肠道内的平衡。这些遗传冲突涉及引起腹泻的肠道病原体， 指导新的研究，旨在重新利用宿主肽变体作为新的抗生素策略。

PROJECT SUMMARY The genomes of microbes and their hosts are intertwined through time. Pathogenic microbes evolve mechanisms to manipulate host cell functions and hosts evolve mechanisms defending from infections. Buried in this evolutionary history of host-microbial conflict are genetically encoded innovations conferring pivotal advantages. Sometimes the discovery of these functions presents an opportunity to harness the process as a research tool. Antibodies, restriction endonucleases, and CRISPR/Cas systems are examples of natural immune processes repurposed to revolutionize modern biology. A central premise of this proposal is to take a similar view of host-microbe conflict as a crucible for biological innovation. Our approach guides rigorous multidisciplinary studies using complementary computational and experimental analysis to investigate diverse host and microbe processes. Our work is revealing a new class of broadly acting antiviral functions. By considering the evolutionary implications of enveloped viruses exploiting the endosomal sorting complex required for transport (ESCRT) pathway, we discovered a new host immune function, encoded by retroCHMP3, that can block the release of maturing virus particles from infected cells. In addition to characterizing the evolutionary process leading to this specific biological innovation, we will develop new computational pipelines to discover related antimicrobial functions in genomes of diverse mammals. The work is also revealing a primary role for retrotransposons and other selfish genetic elements in creating and regulating genes involved in host-virus conflicts. New discoveries related to the activity of selfish genes also applies to our work on DNA virus evolution. Using vaccinia virus as a model system for large DNA virus evolution, we are pursuing several experimental schemes revealing mechanisms of virus adaptation. One example tackles the question of how viruses acquire host genes through horizontal transfer, a mechanism of adaptation common in diverse virus classes. Discovering a primary role for retrotransposons in mobilizing host transcripts to virus genomes connects classic work on phage transduction in bacteria with eukaryotic systems and opens a range of new questions related to virus control of genetic exchange among diverse species. Finally, we will extend our studies to host systems outside dedicated immune defenses, including a project studying intriguing signals of rapid evolution in proteins regulating water balance in the intestine. These genetic conflicts involve enteric pathogens causing diarrhea and guide new studies aimed at repurposing host peptide variants as novel antibiotic strategies.