Evolutionary innovations from host-microbe interactions

项目总结 随着时间的推移，微生物及其宿主的基因组相互交织在一起。病原微生物 进化机制以操纵宿主细胞功能和宿主进化防御机制 不受感染。埋藏在宿主-微生物冲突的进化史中的是遗传 赋予关键优势的编码创新。有时，这些功能的发现 提供了一个将这一过程作为研究工具加以利用的机会。抗体，限制 核酸内切酶和CRISPR/Cas系统是自然免疫过程的例子 改变了用途以彻底改变现代生物学。这项提议的一个核心前提是采取一种 类似的观点认为，宿主与微生物之间的冲突是生物创新的熔炉。我们的方法指导 使用互补的计算和实验分析进行严格的多学科研究 调查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含义 利用运输所需的内体分选复合体(ESCRT)途径，我们 发现了一种新的宿主免疫功能，由RetrochMP3编码，可以阻止释放 来自受感染细胞的成熟病毒颗粒。除了描述进化过程之外 导致这一特定的生物创新，我们将开发新的计算管道来 在不同哺乳动物的基因组中发现相关的抗微生物功能。这项工作也是 揭示了反转录转座子和其他自私的遗传元件在创造和 调节宿主-病毒冲突中涉及的基因。与自私活动相关的新发现 基因也适用于我们在DNA病毒进化方面的工作。以痘苗病毒为模型系统 对于大型DNA病毒的进化，我们正在进行几个实验计划，揭示 病毒适应机制。一个例子解决了病毒如何获取宿主的问题 基因通过水平转移，这是一种在不同类别的病毒中常见的适应机制。 发现反转录转座子在动员宿主转录物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，并打开了一种 与不同物种间遗传交流的病毒控制有关的一系列新问题。 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， 包括一个研究调节水分的蛋白质快速进化的有趣信号的项目 在肠道中保持平衡。这些基因冲突涉及肠道病原体导致腹泻和 指导新的研究，旨在将宿主多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.