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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 CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 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 ?... Life-threatening infections of childhood: Single-gene inborn errors of immunity? Genetic cases of lifethreatening infections 100% Single-gene defects Polygenic/Complex predisposition Age Puberty Primary infection Secondary infection/Reactivation Tuberculosis and other mycobacterial diseases Mycobacteria CYBB IRF8 IL-12 p35 p40 NEMO CD40 IL-12R1 IL-12R2 CD40L IFN-gR1 STAT-1 IFN-gR2 (GAF) Monocyte/Dendritic Cell IFN-g T Lymphocyte Invasive pneumococcal disease IL-1Rs TLRs 1 UNC-93B TLR3 TRIF ? 7 8 9 2 4 5 6 10 1 18 33 MyD88 IRAK-4 Invasive pneumococcal disease Herpes simplex encephalitis IL-1Rs TLRs 1 UNC-93B TLR3 TRIF 7 8 9 2 4 5 6 10 1 18 33 MyD88 IRAK-4 TRAF3 Herpes simplex encephalitis Invasive pneumococcal disease Mucocutaneous candidiasis 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. New targets: fulminant viral hepatitis, acute viral myocarditis, etc. New technologies: deep sequencing, stem cells, etc.
