Jean-Laurent Casanova

Introduction

          The Human Genetics of Infectious Diseases laboratory headed by Jean Laurent Casanova and Laurent Abel is working on the genetic predisposition to infectious diseases on the concept that single-gene inborn errors of immunity in children may confer severe and selective vulnerability to certain infectious illnesses, whereas chronic infections in adults result more from complex inheritance. This work not only blurs the distinction between patient-based Mendelian genetics and population based complex genetics but also provides experimental support for a unified genetic theory of human infectious diseases.

Realizations

         Since the 1950s and until recently, it was believed that mutations in a single gene confer vulnerability to multiple infectious diseases. Dr. Casanova’s team aims to understand what it is that makes some children develop a severe and selective clinical illness in the course of infection while others exposed to the same microbe remain unharmed, by identifying monogenic “holes” in the immune defense of children who are susceptible to specific infectious diseases.

          Dr. Casanova’s team has already identified inborn errors of immunity conferring increased susceptibility to specific pathogens. Examples include the discovery of the molecular genetic basis of predisposition to mycobacterial diseases (mutations of the IL-12-IFN-γ-STAT1 circuit), invasive pneumococcal disease (mutations of the TIR-IRAK4-MyD88-NF-kB pathway), herpes simplex encephalitis (mutations of the TLR3-UNC93B1-IFN-α/β pathway) and chronic mucocutaneous candidiasis (mutations of the IL-17 circuit). In this context, Dr. Casanova and his colleague Dr. Abel also discovered the first cases of Mendelian predisposition to tuberculosis in children and the first major susceptibility locus for this disease in adults.

Immunological impact

          This work strongly supports the notion of a continuous spectrum of genetic susceptibility to infectious diseases, ranging from Mendelian predisposition in children (during primary infection) to complex predisposition in adults (during reinfection or reactivation from latency). The laboratory is now focused on testing the hypothesis that life-threatening infectious diseases of childhood result from collections of rare single-gene inborn errors of immunity.

          Altogether, the discoveries revealed that many immunological circuits that were thought to play a broad role in host defense are largely redundant and essential for immunity against only one or a few specific infections. Dr. Casanova and Dr. Abel hope to decipher the genetic basis of several infectious diseases, thereby defining the function of host defense genes in the natural ecosystem in which human populations live and are subjected to natural selection.

Clinical impact

          Revealing monogenic holes in the immune defense of otherwise healthy children also has profound clinical implications, offering many families worldwide the possibility of molecular diagnosis and genetic counseling as well as treatments aimed at restoring a deficient immune response. Children with impaired IFN-γ production, for example, are prone to tuberculosis and benefit from IFN-γ, whereas patients with impaired IFN-α/β production are prone to herpes simplex encephalitis and may benefit from IFN-α.