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St. Giles Laboratory of Human Genetics of Infectious Diseases

Jean-Laurent Casanova, M.D., Ph.D.
Senior Attending Physician

Dr. Casanova studies the human genetic determinism of pediatric infectious diseases, particularly mycobacterial diseases, invasive pneumococcal disease, herpes simplex encephalitis and chronic mucocutaneous candidiasis. He is interested in identifying monogenic “holes” in the immune defense of otherwise healthy children who are susceptible to specific infectious diseases, work that has profound implications for and has resulted in a paradigm shift in clinical medicine and fundamental immunology.

Dr. Casanova’s laboratory aims to understand what it is that makes some children develop a severe clinical illness in the course of infection while others exposed to the same microbe remain unharmed. The laboratory revealed that single-gene inborn errors of immunity in children may confer severe and selective vulnerability to certain infectious illnesses, whereas corresponding 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.

Since the 1950s and until recently, it was believed that mutations in a single gene confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections have been associated with the inheritance of multiple susceptibility genes (multiple genes, one infection). Dr. Casanova and Dr. Laurent Abel identified and characterized new genetic defects that predispose otherwise healthy individuals to a single type of infection (one gene, one infection), a novel causal relationship that modified the paradigm that had dominated the field for decades.

Dr. Casanova’s team has 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--STAT-1 circuit), invasive pneumococcal disease (mutations of the TIR-IRAK4-MyD88-NF-B pathway), herpes simplex encephalitis (mutations of the TLR3-UNC93B1-IFN-/ pathway) and chronic mucocutaneous candidiasis (mutations in the IL-17 circuit). In parallel, Dr. Abel’s team showed that several common infections, such as schistosomiasis and leprosy, reflect the inheritance of major susceptibility genes, as defined by segregation and/or linkage studies, at least in some populations.

In this context, Dr. Casanova and his colleague Dr. Abel discovered the first cases of Mendelian predisposition to tuberculosis in children and the first major susceptibility locus for this disease in adults. 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 principally 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 have impacted immunology, as they 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 natura, i.e., in the natural ecosystem in which human populations live and are subjected to natural selection.

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- production, for example, are prone to tuberculosis and benefit from IFN-, whereas patients with impaired IFN-/ production are prone to herpes simplex encephalitis and may benefit from IFN-.

Jean-Laurent Casanova, M.D., Ph.D. Senior Attending PhysicianProfessorDr. Casanova studies the human genetic determinism of pediatric infectious diseases, particularly mycobacterial diseases, invasive