Dr. Casanova studies the human genetic determinism of pediatric infectious diseases, including viral, bacterial, and fungal infections. He is interested in identifying single-gene mutations that compromise the immunity of otherwise healthy children and young adults who are vulnerable to specific infectious diseases.
Dr. Casanova’s laboratory aims to understand what it is that makes some children develop a severe clinical illness in the course of infection, whereas others exposed to the same microbe remain unharmed. Work in the laboratory revealed that single-gene inborn errors of immunity in children, adolescents, and young adults may confer severe and selective vulnerability to certain infectious illnesses during primary infection. Meanwhile, corresponding illnesses during secondary infections, typically in older patients, often result more from complex inheritance mechanisms. This work provides theoretical and experimental support for a human genetic theory of infectious diseases.
With Laurent Abel at the Imagine Institute of the Necker Hospital for Sick Children in Paris, Dr. Casanova’s work identifying and characterizing these genetic defects has modified the field’s dominant paradigm, which for decades has associated rare single-gene defects to vulnerabilities to multiple infectious diseases and multiple genetic variations to common infectious diseases.
Dr. Casanova’s team has identified inborn errors of immunity conferring increased susceptibility to a variety of pathogens. Examples include the discovery of the molecular genetic basis of predisposition to mycobacterial diseases (mutations of IFN-γ immunity), invasive pneumococcal disease (mutations of the NF-κB pathway), herpes simplex encephalitis (mutations of the TLR3 pathway), and chronic mucocutaneous candidiasis (mutations of IL-17 immunity).
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, in some populations. In this context, Drs. Casanova and Abel discovered the first cases of monogenic predisposition to tuberculosis in children and the first major susceptibility locus for this disease in adults. This work supports the notion of a continuous spectrum of genetic susceptibility to infectious diseases, ranging from monogenic predisposition in children (during primary infection) to complex predisposition in adults (during reinfection or reactivation from latency).
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. They contribute to defining the function of host defense genes 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-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 or severe influenza and may benefit from IFN-α.
Dr. Casanova is a faculty member in the David Rockefeller Graduate Program and the Tri-Institutional M.D.-Ph.D. Program.