USE OF BACTERIOPHAGE IN PREVENTION, DIAGNOSIS, AND TREATMENT OF HUMAN DISEASES

噬菌体如大肠杆菌噬菌体λ已经被发现。 作为研究的模型系统， 基因调控和大分子组装等主题的研究。我们有 利用Lambda和相关信息的基础 有两个目的： (1)诱变剂和致癌物的检测：我们开发了一种新的检测方法 用于检测小鼠中含有的λ转基因中的突变。 该测定选择仅在噬菌体中含有正向突变的噬菌体。 Lambda cII基因，使用突变体（hfl）大肠杆菌宿主。此外 相对于直接选择的相对容易，该测定的灵敏度 对于自发和化学诱导突变， 广泛使用的突变靶基因lacI，使得cII测定法 用于任何基于λ的突变体噬菌体回收的有吸引力的替代方案 小鼠致突变试验系统。此外，我们的分析成本低80倍 更好的方法。我们的cII分析系统现在正在使用 作为lacI系统的替代品。 (2)噬菌体治疗：多药耐药的流行率增加， 耐药细菌病原体促使我们试图提高 噬菌体的治疗效果。的治疗应用 哺乳动物的抗菌能力阻碍了抗生素的应用 宿主防御系统从循环系统中清除噬菌体颗粒 系统在我们涉及菌血症小鼠的研究中， 消除由主机防御系统，我们开发了一个串行通道 技术在小鼠中选择噬菌体突变体能够留在 循环系统的时间更长，隔离时间更长， 循环突变株E.大肠杆菌噬菌体λ和沙门氏菌 鼠伤寒噬菌体P22。我们证明了长循环λ 突变体作为抗菌剂的能力也比 在感染致死剂量的 细菌亲本和突变体λ衣壳蛋白的比较 揭示了相关的突变改变了噬菌体的主要头部， 蛋白E。 慢性感染性肠球菌经常以 对万古霉素有抗药性我们已经分离出了 噬菌体和细菌素杀死这种耐药菌株。

Bacteriophages such as the Escherichia coli phage lambda have been studied extensively for several decades as model systems for the study of such topics as gene regulation and macromolecular assembly. We have taken advantage of the base of information about Lambda and related phages for two purposes: (1) Detection of mutagens and carcinogens: We developed a novel assay for the detection of mutations in a Lambda transgene contained in mice. The assay selects for phage containing forward mutations only in the Lambda cII gene, using a mutant (hfl) Escherichia coli host. In addition to the relative ease of direct selection, the sensitivity of this assay for both spontaneous and chemically induced mutation was comparable to the widely used mutational target gene lacI, making the cII assay an attractive alternative for mutant phage recovery for any Lambda-based mouse mutatgenesis assay system. Moreover, our assay costs 80 times less to use than the lacI system. Our cII assay system is now being used worldwide as a replacement for the lacI system. (2) Bacteriophage therapy: The increased prevalence of multidrug- resistant bacterial pathogens motivated us to attempt to enhance the therapeutic efficacy of bacteriophages. The therapeutic application of phages as antibacterial agents was impeded by the capacity of mammalian host defense systems to remove phage particles from the circulatory system. In our studies involving bacteremic mice, to reduce phage elimination by the host defense system, we developed a serial-passage technique in mice to select for phage mutants able to remain in the circulatory system for longer periods of time and isolated long- circulating mutants of E. coli phage Lambda and of Salmonella typhimurium phage P22. We demonstrated that the long-circulating Lambda mutants also have greater capability as antibaceterial agents than the corresponding parental strain in animals infected with lethal doses of bacteria. Comparison of the parental and mutant Lambda capsid proteins revealed that the relevant mutation altered the major phage head protein E. Chronically infective Enterococcus species are frequently found in forms resistant to the drug Vanomycin. We have isolated and are characterizing bacteriophages and bacteriocins that kill such drug resistant strains.