Bacteriophages such as theEscherichia 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 overexpression of the new gene causes an increase in the frequency of mutagenesis and a change in the spectrum of mutations. The system has been licensed to Strategene and Epicentre for marketing, and has been licensed to a University of Georgia commercial enterprize to study mutagenesis in fish. (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, we have currently extended such studies to multidrug resistant pathogenic bacteria. Useful phages have been isolated from Mongomery County sewage for the drug resistant bacterial strains. Chronically infective Enterococcus species are frequently found in forms resistant to the drug Vancomycin. We have isolated and are characterizing bacteriophages and bacteriocins that kill such drug resistant strains. The DNA from one potent Enterococcus phage is being sequenced to indentify the encoded genes. - Animal models, Bacterial genetics, Genetics, Mutagenesis, Transgenic Mice, - Neither Human Subjects nor Human Tissues
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