1. 1 Studying host-pathogen interactions with a clinical perspective Marc LECUIT, MD PhD Institut Pasteur, Inserm Hôpital Necker-Enfantsmalades, Université Paris-Descartes

2. Studying host-pathogen interactionsis critically needed on a clinical standpoint Ongoing outbreak of Hemolytic-Uremic Syndrome in Germany Shiga toxin-producing E. coli O104:H4 STX recognizes Gb3Cer/CD77 receptor Species- and tissue-specific Expressed on human endothelial cells STX blocks protein synthesis Endothelial cell damages, cell death Activation of complement cascade Coagulopathy, leading to HUS Therapeutic options Antimicrobial therapy: the outbreak strain is multi-resistant (ESBL-producing strain) Targeted therapy: blockade of complement cascade with an anti-C5 monoclonal antibody 2 Lapeyraqueet al. N Engl J Med, May 2011

3. Key questions we address 3

5. STEC, C. diphtheriae, Neisseria, Shigella, Salmonella, Streptococcus pyogenes, …

6. Poliovirus, Measles virus, HIV, HCV, …

7. Species specificity of Listeria monocytogenes,and its molecular basisL.monocytogenes Guinea pig Rabbit Mouse Rat Human Lecuit et al, EMBO J 1999 Khelef et al, Cell Microbiol 2006 4

9. Rational design of relevant animal models for human infectious diseases

10. Humanized models (transgenesis, knock-in), naturally permissive species

11. Overcome species specificity, discover new ones, iterative processL.monocytogenes E16P mEcad Guinea pig Rabbit Humanized E16P mouse Human Gerbil Lecuit et al, Science 2001 Disson et al, Nature 2008

13. Listeria monocytogenes

14. Intestinal barrier (InlA-Ecad)

15. Placental barrier (InlA-Ecad, InlB-Met)

16. Group B streptococcus

17. ST-17 clone hypervirulence

18. Enhanced crossing of intestinal and blood-brain barriers (HvgA)

19. Translation to emerging infections

20. Chikungunyavirus

21. Animal model

22. CHIKV organ, tissue and cell tropisms

23. Species-specific host response: non-hematopoietic type-I IFN

24. Treatment: passive immunotherapy (CHIKVIgs), antivirals (RNAi)Lm Lm GBS Lecuit et al, Science 2001 Disson et al, Nature 2008 Taziet al, J Exp Med 2010 Couderc et al, PLoS Path 2008 Schilteet al, J Exp Med 2010 Couderc et al, J Infect Dis 2009

26. Laboratory, environmental vs. clinical strains

27. National Reference Centers

28. Whole genome sequencing of hundreds of isolates

29. Genomic and transcriptomic signatures of pathogenicity

30. Host diversity

31. Population exposed: susceptible vs. resistant host

32. Genome: high throughput whole-exome sequencing

33. Microfloraand resulting effects on pathogens and tissues

34. Age: neonates vs. elderly

35. Treatment: antibiotherapy, immunosuppressive therapy

36. Prospective studies

37. Ongoing case-control study on listeriosis (MONALISA)Ragonet al, PLoS Path 2008 Chenal-Francisque, Emerg Infect Dis 2011

39. Microbial side

40. Host side

41. Environment (microbial and non-microbial)

42. Classical and emerging pathogens

43. Listeria monocytogenes, Group B streptococcus

44. Chikungunya and emerging pathogens to come…

45. Pathogen discovery program (PathoDisc)

46. Basic understanding of biological principles

47. Diagnosis, biomarkers, treatment, preventionHôpital Necker-Enfantsmalades