Structural and functional understanding of bacterial defense and viral counter defense

项目总结 病毒通常被认为是破坏剂，必须由宿主有效地清除 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(估计为每秒1023次感染)是将新基因传递给幼稚的主要机制 主持人。因此，病毒在进化过程中扮演着复杂的角色，既是疾病的主要来源，也是 降低死亡率，同时为细胞界提供新的基因创新机会。 在细菌中，病毒(即噬菌体)是赋予毒力和抗生素耐药性的基因的主要提供者， 从而在细菌致病机制的进化中发挥重要作用。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进化和生态的影响 社区。我们有兴趣了解平衡寄主保存的动态过程 (对致命感染的防御)具有对外来DNA进行采样以获得选择性优势特征的优点。 具体地说，这项提案中概述的工作旨在确定两种进化的机制 不同的免疫系统都依赖小RNA或小DNA向导进行序列特异性识别 入侵的遗传因素。该提案分为两个项目，着眼于开发新工具 在分子生物学和医学方面的应用。项目1的重点是了解物种的系统发育和 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旨在了解细菌和古菌中Argavite蛋白的功能多样性。 这项研究的结果将提供机械的见解，有助于我们的长期目标，并具有 这些精密基因组工程新兴工具近期应用的意义。

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.