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.
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