Jean-Laurent Casanova, M.D., Ph.D.
Investigator, Howard Hughes Medical Institute
Senior Attending Physician
Casanova studies the human genetic determinism of pediatric infectious diseases, including viral, bacterial, fungal, and parasitic infections. He is interested in identifying single-gene mutations that compromise the immunity of otherwise healthy children, adolescents, and young adults who are vulnerable to specific infectious diseases.
Casanova’s laboratory aims to understand why some children, adolescents, and young adults develop a severe clinical illness in the course of infection, while most people exposed to the same microbe remain unharmed. Work in the laboratory has revealed that single-gene inborn errors of immunity in young people can confer severe and selective vulnerability to certain infectious illnesses during primary infection. Conversely, the genetic basis of corresponding illnesses during secondary infections that typically occur in older patients is unclear and may 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, 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. Abel is leading the mathematical “dry lab” at Necker and Rockefeller, whereas Casanova heads the experimental “wet lab” in both locations.
Casanova’s team has identified inborn errors of immunity conferring increased susceptibility to a variety of pathogens. For example, they discovered that mutations in IRF7 provide the molecular genetic basis for a predisposition to severe influenza. Likewise, they have found that errors in IL-17 immunity confer unusual vulnerability to chronic mucocutaneous candidiasis; that disruptions in the TLR3 pathway predispose patients to herpes simplex encephalitis; and that mutations in CARD9 contribute to invasive fungal disease.
In identifying errors in IFN-γ immunity responsible for a vulnerability to mycobacterial infections, Casanova and Abel discovered the first cases of monogenic predisposition to tuberculosis in children.
These discoveries have revealed that many immunological circuits that were previously thought to play a broad role in host defense are largely redundant and essential for immunity against one or a few specific infections only. 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.