1. 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

2. 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 ?...

3. 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?

4. 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

5. 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

6. 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

7. Mucocutaneous candidiasis