Bacteriophage diversity, dynamics, function, and exploitation

噬菌体是地球上数量最多的生物实体。噬菌体数量是巨大的 动态的，每隔几天通过感染和繁殖进行自我更新，可能超过30亿 很多年了。不足为奇的是，它们在基因上是巨大的多样性，尽管这种多样性仍然定义不清 而且只有一小部分噬菌体种群被基因组学研究过。 噬菌体在环境、人类健康和生物技术中扮演着重要的角色。他们是 通过编码毒素与许多细菌疾病有关，并调节各种细菌的生理 方式。它们的多样性部分是由高度动态的微生物群落产生的，其中有 细菌在病毒感染的持续攻击中生存下来的巨大选择压力，以及 噬菌体通过突变感染新的细菌宿主或进化反防御系统来共同进化 克服阻力。细菌用来抵御噬菌体感染的防御系统包括限制- 改良和CRISPR-CAS系统，这两个系统都在生物技术和 基因组工程。它们的巨大影响部分源于它们非凡的效率和 特殊性，是30亿年来高度动态进化的结果。 细菌病原体普遍存在的抗生素耐药性问题日益严重，这是一个全球性的重大问题 健康风险。解决这一问题需要新的治疗方法的创新战略，以及积极的 寻找新的抗菌剂。噬菌体疗法的前景已经被设想 已有近100年的历史，但在美国尚未得到广泛使用。由门中的病原体引起的疾病 放线杆菌，包括结核和囊性纤维化患者的NTM感染，是值得注意的公共卫生问题 挑战，但任何治疗性噬菌体干预的前景都需要了解 噬菌体宿主范围的决定因素以及噬菌体抗性的机制和特异性。 感染放线杆菌宿主的13,000多个噬菌体的大集合，其中2,500个完全 测序，为研究噬菌体多样性、噬菌体基因组进化、噬菌体宿主提供了强大的资源 范围，细菌噬菌体动力学，结核病和非结核杆菌感染的遗传和临床工具。许多. 这些噬菌体是温和的，它们编码防御系统，这些系统由原噬菌体表达，并抑制 不同(即异型)噬菌体感染溶原菌。这些防御系统多种多样，而且大多数 的基因没有生物信息预测的功能。防御通常是针对少数几个子集 噬菌体，但靶向机制尚不清楚。 噬菌体的多样性、进化、动态和抗性的特征将有助于发展 细菌感染的新诊断、预防和治疗方法。

Bacteriophages are the most numerous biological entities on the planet. The phage population is enormously dynamic, replacing itself through infection and reproduction every few days, and may be more than three billion years old. Not surprisingly, they are enormously diverse genetically, although this diversity remains ill-defined and only an extremely small part of the phage population has been genomically explored. Bacteriophages play prominent roles in the environment, in human health, and in biotechnology. They are implicated in many bacterial diseases by coding for toxins, and modulate bacterial physiology in a variety of ways. Their diversity is generated in part by the highly dynamic microbial community in which there is enormous selective pressure for bacteria to survive the constant onslaught of viral infections, and for the phages to co-evolve by mutating to infect new bacterial hosts or evolving counter-defense systems that overcome resistance. Among the defense systems that bacteria use to fight off phage infection are restriction- modification and CRISPR-Cas systems, both of which have played revolutionary roles in biotechnology and genome engineering. The huge impact of these derives in part from their extraordinary efficiency and specificity, the consequences of three billion years of highly dynamic evolution. The growing problem of widespread antibiotic resistance by bacterial pathogens presents a substantial global health risk. Addressing this requires innovative strategies for new therapeutic approaches, and an aggressive search for new antimicrobial agents. The prospects of bacteriophage therapy have been contemplated for nearly 100 years, but has not found widespread use in the US. Diseases caused by pathogens in the phylum Actinobacteria, including tuberculosis and NTM infections of Cystic Fibrosis patients, are notable public health challenges, but any prospects for therapeutic phage interventions requires an understanding of the determinants of phage host range and the mechanisms and specificity of phage resistance. A large collection of over 13,000 phages infecting Actinobacterial hosts, 2,500 of which are completely sequenced, provide a powerful resource for investigating phage diversity, phage genome evolution, phage host range, bacterial-phage dynamics, and genetic and clinical tools for tuberculosis and NTM infections. Many of these phages are temperate, and code for defense systems that are prophage-expressed and inhibit the infection of lysogens by different (i.e. heterotypic) phages. These defense systems are highly varied and most of the genes do not have bioinformatically predicted functions. Defense is often specific for a few subset of the phages, but the mechanisms of targeting is not known. The characterization of phage diversity, evolution, dynamics, and resistance will facilitate the development of new diagnostic, preventative, and therapeutic approaches for bacterial infections.