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Molecular interactions between hosts and pathogens Partho Ghosh

Molecular interactions between hosts and pathogens Partho Ghosh Department of Chemistry & Biochemistry and Section of Molecular Biology University of California, San Diego http://pghosh.ucsd.edu. Infectious Diseases at the Molecular Level. Virulence Factors. Host Cell Target.

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Molecular interactions between hosts and pathogens Partho Ghosh

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  1. Molecular interactions between hosts and pathogens Partho Ghosh Department of Chemistry & Biochemistry and Section of Molecular Biology University of California, San Diego http://pghosh.ucsd.edu

  2. Infectious Diseases at the Molecular Level Virulence Factors Host Cell Target Establishment of niche in host Subversion of host defenses and immunity Proliferation in host Transmission to other hosts Pathogens Host cells

  3. Type III Secretion Needles Human cell Pathogenic bacterium Kubori et al., Science 280:602 (98)

  4. Type III Secretion System (TTSS) • Pathogens of plants • Erwinia amylovora • Pseudomonas syringae • Ralstonia solanacearum • Xanthomonas campestris Gram-negative Pathogens of mammals Escherichia coli Pseudomonas aeruginosa Salmonella tymphimurium Shigella flexneri Bordetella pertussis Chlamydia trachomatis Yersinia spp.

  5. Ubiquitous and antibiotic-resistant bacterium • Problem for patients with weakened immune systems Pseudomonas aeruginosa CDC • Certain strains cause severe and acute infections • 90% of severe and acute strains • — inject the protein ExoU into human cells, results in cell death

  6. How does ExoU function? Using genome sequences to get the answer Phospholipase A2 motifs — destroy mammalian cell membranes But, overall identity to phospholipase ~10% Phillips et al. JBC (03)

  7. Testing the phospholipase idea: Syringe Loading 106 mammalian cells + ExoU ? Clarke & McNeil. (1992) J Cell Sci 102:533-41

  8. ExoU kills mammalian cells and needs sites 1 and 2 Cell Death Site 1 ExoU Site 2

  9. ExoU needs a mammalian cell component ExoU-GFP

  10. Learning what that component is using yeast Yeast without ExoU Yeast making ExoU

  11. ExoU kills cells but Phospholipase inhibitors block cell death Cell Death Inhibitors

  12. Will inhibitors stop Pseudomonas? Pseudomonas aeruginosa + inhibitor

  13. Inhibitors protect against Pseudomonas Cell Death Pseudomonas w/o ExoU Pseudomonas Pseudomonas + Inhibitor

  14. UCSD Ed Dennis David Six Lorraine Pillus William Fenical University of Toronto Charlie Boone Funding W.M. Keck Foundation Cystic Fibrosis Foundation Current Ann Cai Alicia Gamez Jyothi Kumaran Case McNamara Jason Miller Rebecca Phillips Catarina Raposo Loren Rodgers

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