Transcript Diapositive 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
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-12R1
IL-12R2
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.