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

噬菌体如大肠杆菌噬菌体lambda已经被 作为研究的模型系统，进行了数十年的广泛研究 如基因调控和大分子组装等主题。我们有 利用有关lambda和相关的信息库 噬菌体用于两个目的： (1)致突变物和致癌物的检测：我们开发了一种新的检测方法 用于检测小鼠体内含有的lambda转基因的突变。 该检测只选择包含正向突变的噬菌体 Lambda CII基因，使用突变的(HFL)大肠杆菌宿主。在……里面 除了直接选择相对容易之外， 这种自发和化学诱导突变的检测方法是 与广泛使用的突变靶基因lacI类似，使 CII试验是一种有吸引力的突变噬菌体回收方法 基于Lambda的小鼠突变检测系统。此外，我们的化验结果 使用成本比LACI系统低80倍。 (2)噬菌体疗法：患病率增加 多重耐药细菌病原体促使我们尝试 增强噬菌体的治疗效果。治疗性 噬菌体作为抗菌剂的应用受到阻碍 哺乳动物宿主防御系统清除噬菌体颗粒的能力 来自循环系统。在我们对细菌血症小鼠的研究中， 为了减少宿主防御系统对噬菌体的清除，我们开发了 小鼠连续传代技术筛选噬菌体突变体 在循环系统中停留的时间更长， 分离的大肠杆菌噬菌体Lambda和Of的长循环突变体 鼠伤寒沙门氏菌噬菌体P22。我们演示了 长循环的lambda突变体也具有更大的能力，如 抗菌药物在动物中比相应的亲本菌株 感染了致死剂量的细菌。父母和父母的比较 突变的lambda衣壳蛋白揭示了相关的突变 改变主要噬菌体头部蛋白E。

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 80X less to use than 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.