Structural and functional understanding of bacterial defense and viral counter defense

项目摘要 病毒通常被认为是破坏剂，其必须被宿主有效地消除， 自我保护然而，病毒也是地球上最大的遗传多样性储存库， 感染（估计每秒1023次感染）是将新基因传递给幼稚细胞的主要机制。 hosts.因此，病毒在进化过程中具有复杂的作用，既是疾病的主要来源， 死亡率，同时为细胞社区提供了基因创新的新机会。 在细菌、病毒（即，是赋予毒力和抗生素抗性的基因的主要提供者， 因此在细菌致病机理的进化中起主要作用。我们研究的长期目标是 了解噬菌体防御系统对人类相关微生物的进化和生态学的影响 社区.我们有兴趣了解平衡宿主保存的动态过程 （防御致命感染），具有对选择性有利性状的外源DNA进行取样的优点。 具体而言，本提案中概述的工作旨在从进化的角度确定两种机制， 不同的免疫系统都依赖于小RNA或小DNA指导序列特异性识别 入侵的遗传因子该提案分为两个项目，着眼于开发新工具 用于分子生物学和医学。项目1的重点是了解系统发育和 抑制CRISPR介导的适应性免疫的噬菌体编码的抗CRISPR的功能多样性 系统.项目2旨在了解Argonaute蛋白在细菌和古细菌中的功能多样性。 这项研究的结果将提供有助于我们长期目标的机制见解， 这些新兴工具对精确基因组工程的近期应用具有重要意义。

PROJECT SUMMARY Viruses are generally considered to be agents of destruction that must be efficiently eliminated by the host for self-preservation. However, viruses are also the largest reservoir of genetic diversity on the planet, and viral infections (estimated 1023 infections per second) are a primary mechanism for delivering new genes to naïve hosts. Thus, viruses have a complex role in the process of evolution, being both a major source of disease and mortality, while simultaneously presenting the cellular community with new opportunities for genetic innovation. In bacteria, viruses (i.e., phages) are major purveyors of genes that confer virulence and antibiotic resistance, and thus play a major role in the evolution of bacterial pathogenesis. The long-term goal of our research is to understand the impact of phage defense systems on the evolution and ecology of human-associated microbial communities. We are interested in understanding the dynamic processes that balance host preservation (defense from lethal infection) with the advantages of sampling foreign DNA for selectively advantageous traits. Specifically, the work outlined in this proposal is aimed at determining the mechanisms of two evolutionarily distinct immune systems that both rely on small RNA or small DNA guides for sequence-specific recognition of invading genetic elements. The proposal is divided into two projects, with an eye toward developing new tools for applications in molecular biology and medicine. Project 1 focuses on understanding the phylogenetic and functional diversity of phage encoded anti-CRISPRs that suppress CRISPR-mediated adaptive immune systems. Project 2 aims to understand the functional diversity of Argonaute proteins in bacteria and archaea. Results from this research will provide mechanistic insights that contribute to our long-term goal and have significance implications in the near-term application of these emerging tools for precise genome engineering.