ceachrucnrscpuinrainriainserminstitut pasteurird lethal infectious diseases of childhood:...
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CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
Lethal infectious diseases of childhood:
Single-gene inborn errors of immunity ?
Jean-Laurent CasanovaHead, St. Giles Laboratory of Human Genetics of Infectious Diseases
Pediatrician, Necker Hospital for Sick Children, Paris, FranceProfessor, The Rockefeller University, New York, USA
1911-1917: The discoveryof inapparent infections
Only 10-7 to 10-1 infected individualsdevelop clinical disease
Microbes are necessary but not sufficient to cause disease
Even in the course of primaryinfections …
What accounts forinter-individual variability ?
What is the pathogenesisof infectious diseases ?...
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?
Monocyte/Dendritic Cell T Lymphocyte
MycobacteriaIL-12R1
IL-12R2
IFN-R1
IL-12p35
p40
IFN-IFN-R2STAT-1
(GAF)
NEMO CD40 CD40L
Tuberculosis and other mycobacterial diseases
IRF8
CYBB
1 2 4 5 6 10
MyD88
IRAK-4
1
TLR3 7 8 9
TRIF
UNC-93B
TLRs IL-1Rs
18 33
Invasivepneumococcaldisease
?
Invasive pneumococcal disease
1 2 4 5 6 10
MyD88
IRAK-4
1
TLR3 7 8 9
TRIF
UNC-93B
TLRs IL-1Rs
18 33
Invasivepneumococcaldisease
Herpessimplexencephalitis
Herpes simplex encephalitis
TRAF3
Mucocutaneous candidiasis
New targets: fulminant viral hepatitis, acute viral myocarditis, etc.
New technologies: deep sequencing, stem cells, etc.
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.