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  1. 1. Bacteriophage
  2. 2. Bacteriophage (Phage) <ul><li>Definition - Obligate intracellular parasites that multiply inside bacteria by making use of some or all of the host biosynthetic machinery </li></ul><ul><li>Significance </li></ul><ul><ul><li>Models for animal cell viruses </li></ul></ul><ul><ul><li>Gene transfer in bacteria </li></ul></ul><ul><ul><li>Medical applications </li></ul></ul><ul><ul><ul><li>Identification of bacteria - phage typing </li></ul></ul></ul><ul><ul><ul><li>Treatment and prophylaxsis??? </li></ul></ul></ul>
  3. 3. Medical Applications of Phage <ul><li>“ I strongly believe phage could become an effective antibacterial tool” - Carl Merril, Chief of the Laboratory of Biochemical Genetics, National Institute of Mental Health, NIH. </li></ul><ul><li>“ It might be another string on the bow, such that when (conventional antibiotics) fail, here’s something that has a chance of working. But it’s not going to be a panacea” - Joshua Lederberg, Sackler Foundation Scholar at The Rockefeller University </li></ul>Reassessment of Medicinal Phage Spurs Companies to Study Therapeutic Uses American Society for Microbiology News 64:620-623, 1998
  4. 4. Medical Applications of Phage <ul><li>Exponential Biotherapies (Rockville, MD) </li></ul><ul><ul><li>Vancomycin resistant Enterococcus facium and Streptococcus pneumoniae </li></ul></ul><ul><li>Phage Therapeutics (Bothell, WA) </li></ul><ul><ul><li>Staphylococcus aureus and Staphylococcus epidermidis </li></ul></ul><ul><li>Intralytix, Inc. (Baltimore, MD) </li></ul><ul><ul><li>Salmonella in meat and poultry </li></ul></ul><ul><li>Biopharm Ltd. (Tblisi, Georgia) </li></ul><ul><ul><li>Infections associated with burns </li></ul></ul><ul><li>University of Idaho </li></ul><ul><ul><li>Escherichia coli O157:H7 in cattle </li></ul></ul>Reassessment of Medicinal Phage Spurs Companies to Study Therapeutic Uses. American Society for Microbiology News 64:620-623, 1998. Phages eyed as agents to protect against harmful E. coli. American Society for Microbiology News 65:666-667, 1999.
  5. 5. Bacteriophage <ul><li>T 4 </li></ul><ul><li>Lambda (  ) </li></ul>
  6. 6. Composition and Structure <ul><li>Composition </li></ul><ul><ul><li>Nucleic acid </li></ul></ul><ul><ul><ul><li>Genome size </li></ul></ul></ul><ul><ul><ul><li>Modified bases </li></ul></ul></ul><ul><ul><li>Protein </li></ul></ul><ul><ul><ul><li>Protection </li></ul></ul></ul><ul><ul><ul><li>Infection </li></ul></ul></ul><ul><li>Structure (T 4 ) </li></ul><ul><ul><li>Size </li></ul></ul><ul><ul><li>Head or capsid </li></ul></ul><ul><ul><li>Tail </li></ul></ul>Tail Tail Fibers Base Plate Head/Capsid Contractile Sheath
  7. 7. Infection of Host Cells <ul><li>Irreversible attachment </li></ul><ul><li>Adsorption </li></ul><ul><ul><li>LPS for T4 </li></ul></ul><ul><li>Nucleic acid injection </li></ul><ul><li>Sheath Contraction </li></ul>
  8. 8. Types of Bacteriophage <ul><li>Lytic or virulent phage: Phage that can only multiply within bacteria and kill the cell by lysis. ( e.g., T 4 ) </li></ul>
  9. 9. Lytic Phage Multiplication Cycle <ul><li>Eclipse </li></ul><ul><ul><li>Early genes </li></ul></ul><ul><ul><li>Phage DNA synthesis </li></ul></ul><ul><ul><li>Late genes </li></ul></ul><ul><li>Intracellular accumulation </li></ul><ul><li>Lysis and Release </li></ul>Total Phage Extracellular Phage Eclipse Intracellular accumulation phase Time after Infection Number of Infectious Particles Lysis
  10. 10. Assay for Lytic Phage <ul><li>Plaque assay </li></ul><ul><ul><li>Method </li></ul></ul><ul><ul><li>Plaque forming unit (pfu) </li></ul></ul><ul><ul><li>Measures infectious particles </li></ul></ul>Bacteria Phage + Phage
  11. 11. Types of Bacteriophage <ul><li>Lysogenic or temperate phage: Phage that can either multiply via the lytic cycle or enter a quiescent state in the bacterial cell. ( e.g.,  ) </li></ul><ul><ul><li>Expression of most phage genes repressed </li></ul></ul><ul><ul><li>Prophage </li></ul></ul><ul><ul><li>Lysogen </li></ul></ul>
  12. 12. Events Leading to Lysogeny <ul><li>Circularization of the phage chromosome </li></ul><ul><ul><li>Cohesive ends </li></ul></ul>Lygase Closed Circle Cohesive Ends Linear Double Stranded Opened Circle
  13. 13. Events Leading to Lysogeny <ul><li>Site-specific recombination </li></ul><ul><ul><li>Phage coded enzyme </li></ul></ul><ul><li>Repression of the phage genome </li></ul><ul><ul><li>Repressor protein </li></ul></ul><ul><ul><li>Specific </li></ul></ul><ul><ul><li>Immunity to superinfection </li></ul></ul>gal bio gal bio gal bio
  14. 14. Termination of Lysogeny <ul><li>Induction </li></ul><ul><ul><li>Adverse conditions </li></ul></ul><ul><li>Role of proteases </li></ul><ul><ul><li>recA protein </li></ul></ul><ul><ul><li>Destruction of repressor </li></ul></ul><ul><li>Excision </li></ul><ul><li>Lytic growth </li></ul><ul><li>Gene expression </li></ul>gal bio gal bio gal bio gal bio
  15. 15. Lytic vs Lysogenic Cycle? <ul><li>Role of repressor </li></ul><ul><li>Role of cro gene product </li></ul><ul><li>Role of proteases </li></ul>
  16. 16. Significance of Lysogeny <ul><li>Model for animal virus transformation </li></ul><ul><li>Lysogenic or phage conversion </li></ul><ul><ul><li>Definition: A change in the phenotype of a bacterial cell as a consequence of lysogeny </li></ul></ul><ul><ul><ul><li>Modification of Salmonella O antigen </li></ul></ul></ul><ul><ul><ul><li>Toxin production by Corynebacterium diphtheriae </li></ul></ul></ul>