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2.1 jean-laurent casanova 2.1 jean-laurent casanova Presentation Transcript

  • Lethal infectious diseases of childhood: Single-gene inborn errors of immunity ? Jean-Laurent Casanova Head, St. Giles Laboratory of Human Genetics of Infectious Diseases Pediatrician, Necker Hospital for Sick Children, Paris, France Professor, The Rockefeller University, New York, USA
  • 1911-1917: The discovery of inapparent infections Only 10 -7 to 10 -1 infected individuals develop clinical disease Microbes are necessary but not sufficient to cause disease Even in the course of primary infections … What accounts for inter-individual variability ? What is the pathogenesis of infectious diseases ?...
  • Puberty Single-gene defects Age Polygenic/Complex predisposition 100% Genetic cases of life-threatening infections Primary infection Secondary infection/Reactivation Life-threatening infections of childhood: Single-gene inborn errors of immunity?
  • Monocyte/Dendritic Cell T Lymphocyte Mycobacteria IL-12R  1 IL-12R  2 IFN-  R1 IL-12 p35 p40 IFN-  IFN-  R2 STAT-1 (GAF) NEMO CD40 CD40L Tuberculosis and other mycobacterial diseases IRF8 CYBB
  • 1 2 4 5 6 10 MyD88 IRAK-4 1 TLR3 7 8 9 TRIF UNC-93B TLRs IL-1Rs 18 33 Invasive pneumococcal disease ? Invasive pneumococcal disease
  • 1 2 4 5 6 10 MyD88 IRAK-4 1 TLR3 7 8 9 TRIF UNC-93B TLRs IL-1Rs 18 33 Invasive pneumococcal disease Herpes simplex encephalitis Herpes simplex encephalitis TRAF3
  • Mucocutaneous candidiasis
      • New targets: fulminant viral hepatitis, acute viral myocarditis, etc.
      • New technologies: deep sequencing, stem cells, etc.
    Conclusions and perspectives
      • Pioneers and leaders in the field of human inborn errors of immunity
      • Aim: dissecting the molecular basis of host defense in natura
      • The genetic theory: the new frontier in infectious diseases
      • Aim: understanding the pathogenesis of infectious diseases (at last)
      • Selected references: Altare et al. , Science 1998; de Jong et al. , Science 1998; Dupuis et al. , Science 2001; Picard et al. , Science 2003; Casrouge et al., Science 2006; Casanova and Abel, Science 2007; Zhang et al., Science 2007; von Bernuth et al. , Science 2008; Puel et al., Science 2011.