1.6 marc lecuit

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1.6 marc lecuit

  1. 1. 1<br />Studying host-pathogen interactions with a clinical perspective<br />Marc LECUIT, MD PhD<br />Institut Pasteur, Inserm<br />Hôpital Necker-Enfantsmalades, Université Paris-Descartes<br />
  2. 2. Studying host-pathogen interactionsis critically needed on a clinical standpoint<br />Ongoing outbreak of Hemolytic-Uremic Syndrome in Germany<br />Shiga toxin-producing E. coli O104:H4<br />STX recognizes Gb3Cer/CD77 receptor<br />Species- and tissue-specific<br />Expressed on human endothelial cells<br />STX blocks protein synthesis<br />Endothelial cell damages, cell death<br />Activation of complement cascade<br />Coagulopathy, leading to HUS<br />Therapeutic options<br />Antimicrobial therapy: the outbreak strain is multi-resistant (ESBL-producing strain)<br />Targeted therapy: blockade of complement cascade with an anti-C5 monoclonal antibody<br />2<br />Lapeyraqueet al. N Engl J Med, May 2011<br />
  3. 3. Key questions we address<br />3<br />
  4. 4. Microbialspeciesspecificity<br /><ul><li>Most pathogens are species-specific
  5. 5. STEC, C. diphtheriae, Neisseria, Shigella, Salmonella, Streptococcus pyogenes, …
  6. 6. Poliovirus, Measles virus, HIV, HCV, …
  7. 7. Species specificity of Listeria monocytogenes,and its molecular basis</li></ul>L.monocytogenes<br />Guinea pig<br />Rabbit<br />Mouse<br />Rat<br />Human<br />Lecuit et al, EMBO J 1999<br />Khelef et al, Cell Microbiol 2006<br />4<br />
  8. 8. Microbialspeciesspecificity<br />5<br /><ul><li>Critical issue for the human relevance of in vitro and in vivo investigations
  9. 9. Rational design of relevant animal models for human infectious diseases
  10. 10. Humanized models (transgenesis, knock-in), naturally permissive species
  11. 11. Overcome species specificity, discover new ones, iterative process</li></ul>L.monocytogenes<br />E16P<br />mEcad<br />Guinea pig<br />Rabbit<br />Humanized<br /> E16P mouse<br />Human<br />Gerbil<br />Lecuit et al, Science 2001<br />Disson et al, Nature 2008<br />
  12. 12. Microbialhost invasionand disseminationinto tissues<br />6<br /><ul><li>Microbial crossing of host barriers
  13. 13. Listeria monocytogenes
  14. 14. Intestinal barrier (InlA-Ecad)
  15. 15. Placental barrier (InlA-Ecad, InlB-Met)
  16. 16. Group B streptococcus
  17. 17. ST-17 clone hypervirulence
  18. 18. Enhanced crossing of intestinal and blood-brain barriers (HvgA)
  19. 19. Translation to emerging infections
  20. 20. Chikungunyavirus
  21. 21. Animal model
  22. 22. CHIKV organ, tissue and cell tropisms
  23. 23. Species-specific host response: non-hematopoietic type-I IFN
  24. 24. Treatment: passive immunotherapy (CHIKVIgs), antivirals (RNAi)</li></ul>Lm<br />Lm<br />GBS<br />Lecuit et al, Science 2001<br />Disson et al, Nature 2008<br />Taziet al, J Exp Med 2010<br />Couderc et al, PLoS Path 2008<br />Schilteet al, J Exp Med 2010<br />Couderc et al, J Infect Dis 2009<br />
  25. 25. 7<br />Microbial and host biodiversity<br /><ul><li>Microbial diversity
  26. 26. Laboratory, environmental vs. clinical strains
  27. 27. National Reference Centers
  28. 28. Whole genome sequencing of hundreds of isolates
  29. 29. Genomic and transcriptomic signatures of pathogenicity
  30. 30. Host diversity
  31. 31. Population exposed: susceptible vs. resistant host
  32. 32. Genome: high throughput whole-exome sequencing
  33. 33. Microfloraand resulting effects on pathogens and tissues
  34. 34. Age: neonates vs. elderly
  35. 35. Treatment: antibiotherapy, immunosuppressive therapy
  36. 36. Prospective studies
  37. 37. Ongoing case-control study on listeriosis (MONALISA)</li></ul>Ragonet al, PLoS Path 2008<br />Chenal-Francisque, Emerg Infect Dis 2011<br />
  38. 38. Perspectives<br />8<br /><ul><li>Holistic view of the infectious process
  39. 39. Microbial side
  40. 40. Host side
  41. 41. Environment (microbial and non-microbial)
  42. 42. Classical and emerging pathogens
  43. 43. Listeria monocytogenes, Group B streptococcus
  44. 44. Chikungunya and emerging pathogens to come…
  45. 45. Pathogen discovery program (PathoDisc)
  46. 46. Basic understanding of biological principles
  47. 47. Diagnosis, biomarkers, treatment, prevention</li></ul>Hôpital Necker-Enfantsmalades<br />

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