The Use of Bacteriophage in the Prevention, Diagnosis, and Treatment of Human Di

噬菌体，如大肠杆菌噬菌体Lambda，作为基因调控、宿主-病毒相互作用和大分子组装等主题研究的模型系统，已经被广泛研究了几十年。我们利用了Lambda和相关噬菌体的基础信息，用于两个目的：(1)检测诱变剂和致癌物：我们开发了一种检测小鼠中Lambda转基因突变的新方法。该试验选择仅在Lambda cII基因中含有正向突变的噬菌体，使用突变体（hfl）大肠杆菌。除了相对容易的直接选择外，该方法对自发突变和化学诱导突变的敏感性与广泛使用的突变靶基因lacI相当。此外，我们的检测成本比lacissystem低80倍。我们的cII检测系统目前在全球范围内被用作lacIsystem的替代品。在与Glenn Merlino博士的合作中，该系统现在被用于研究突变在癌症发展中的作用，并且似乎新基因的表达导致突变谱的变化(2)噬菌体治疗：多药耐药细菌病原体的日益流行促使我们尝试提高噬菌体的治疗效果。哺乳动物宿主防御系统从循环系统中清除噬菌体颗粒的能力阻碍了噬菌体作为抗菌剂的治疗应用。在我们涉及致菌小鼠的研究中，为了减少宿主防御系统对噬菌体的消除，我们之前分离了大肠杆菌噬菌体Lambda和沙门氏菌噬菌体P22突变体，它们能够在循环系统中停留更长的时间，并且在感染致死剂量细菌的动物中具有更大的抗菌能力。Lambda的突变发生在主要衣壳蛋白的基因中。在与Carl merrill博士和Dean Scholl博士的合作中，我们现在已经分离出一种DNA噬菌体，它能够感染带有K抗原的致病性大肠杆菌。与先前分离的噬菌体fK1-5不同，它含有两种类型的尾部，使其能够在具有K1和K5抗原的宿主上生长。

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, host-virus interactions, 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 colihost. 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. Moreover, our assay costs 80 times less to use than the lacIsystem. Our cII assay system is now being used worldwide as a replacement for the lacIsystem. In a collaboration with Dr. Glenn Merlino, the system is now being used to study the role of mutagenesis in cancer development and it appears that expression of the new gene causes a change in the spectrum of mutations(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 previously isolated E. coli phage Lambda and Salmonella phage P22 mutants able to remain in the circulatory system for longer periods of time and also have greater capability as antibaceterial agents in animals infected with lethal doses of bacteria. The mutations in Lambda are in the gene for the major capsid protein. In a collaboration with Dr. Carl Merril and Dr. Dean Scholl, we have now isolated and characterized a DNA bacteriophage capable of infecting pathogenic Escherichia coliwith K antigens. The phage, fK1-5, ulike previously isolates, contain two types of tails enabling it to grow on both hosts with K1 and K5 antigens.