1. 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

2. of inapparent infections
: 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. 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

4. 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

5. 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 ?

6. 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

7. Mucocutaneous candidiasis

8. 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.
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