Heads of Laboratories
Investigator, Howard Hughes Medical Institute
Senior Attending Physician
St. Giles Laboratory of Human Genetics of Infectious Diseases
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.
Ph.D. in biology, 1992
University Paris Pierre et Marie Curie
University Paris Descartes
Clinical and Research Fellow, 1996–1999
Assistance Publique-Hôpitaux de Paris
Visiting Professor, 2008–
Necker Hospital and School of Medicine, University Paris Descartes
Senior Attending Pediatrician, 1999–2008
Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris
The Rockefeller University
Senior Attending Physician, 2008–
The Rockefeller University Hospital
International Research Scholar, 2005–2008
Howard Hughes Medical Institute
Professor Lucien Dautrebande Pathophysiology Foundation Prize, 2004
Richard Lounsbery Award, 2008
E. Mead Johnson Award, Society for Pediatric Research, 2010
InBev Baillet-Latour Health Prize, 2011
Ilse and Helmut Wachter Foundation Award, 2012
Milstein Award, 2012
Robert Koch Award, 2014
Sanofi–Institut Pasteur Award, 2014
Presidential Award, Clinical Immunology Society, 2014
Norman J. Siegel Award, American Pediatric Society, 2014
Stanley J. Korsmeyer Award, American Society for Clinical Investigation, 2016
Foreign Associate, National Academy of Sciences
National Academy of Medicine
Ciancanelli, M.J. et al. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science 348, 448–453 (2015).
Bolze, A. et al. Ribosomal protein SA haploinsufficiency in humans with isolated congenital asplenia. Science 340, 976–978 (2013).
Bogunovic, D. et al. Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency. Science 337, 1684–1688 (2012).
Puel, A. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011).
von Bernuth, H. et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321, 691–696 (2008).