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.