Lethal infectious diseases of childhood: Single-gene inborn errors of immunity ? Jean-Laurent Casanova Document à remplir en anglais Thématique de l’équipe Nom du scientifique Affiliation Localisation 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 1

of inapparent infections 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 life-threatening infections 100% Single-gene defects Polygenic/Complex predisposition Age Puberty Primary infection Secondary infection/Reactivation 3 3

Tuberculosis and other mycobacterial diseases Monocyte/Dendritic Cell IL-12 IL-12R1 p35 CYBB p40 IL-12R2 IRF8 NEMO CD40 CD40L IFN-gR1 STAT-1 (GAF) IFN-gR2 IFN-g Monocyte/Dendritic Cell T Lymphocyte

Invasive pneumococcal disease TLRs IL-1Rs 1 2 4 5 6 10 1 18 33 UNC-93B MyD88 TLR3 7 8 9 IRAK-4 TRIF Invasive pneumococcal disease ?

Herpes simplex encephalitis TLRs IL-1Rs 1 2 4 5 6 10 1 18 33 UNC-93B MyD88 TLR3 7 8 9 IRAK-4 TRIF 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. Rappeler le nom du directeur d’équipe/de laboratoire et le titre Indiquer entre 3 et 5 perspectives d’étude liée à la thématique de l’équipe/du laboratoire