Heads of Laboratories
Dr. Casanova studies the human genetic determinism of pediatric infectious diseases, particularly mycobacterial diseases, invasive pneumococcal disease, herpes simplex encephalitis, chronic mucocutaneous candidiasis, severe flu and Kaposi sarcoma. 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 populationbased 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, whereas common infections have been associated with the inheritance of multiple susceptibility genes. Dr. Casanova and Laurent Abel identified and characterized new genetic defects that predispose otherwise healthy individuals to a single type of 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-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 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 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.
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.
Dr. Casanova received his M.D. from the University of Paris Descartes in 1987. He received his Ph.D. in immunology from the University of Paris Pierre and Marie Curie in 1992, after being trained at the Pasteur Institute in Paris and the Ludwig Institute for Cancer Research in Lausanne. Following a residency in pediatrics and a clinical fellowship in pediatric immunology-hematology, he was appointed a professor of pediatrics at the Necker Medical School in Paris. There, with Dr. Abel, he cofounded and codirected the Laboratory of Human Genetics of Infectious Diseases in 2001. He was appointed professor at Rockefeller in 2008 and named a Howard Hughes Medical Institute investigator in 2013.
Dr. Casanova was an international research scholar with the Howard Hughes Medical Institute from 2005 to 2008 and was elected to the European Molecular Biology Organization in 2005. Dr. Casanova was the recipient of the Professor Lucien Dautrebande Pathophysiology Foundation Prize in 2004, the Richard Lounsbery Award in 2008, the Oswald Avery Award from the Infectious Disease Society of America in 2009, the E. Mead Johnson Award from the Society for Pediatric Research in 2010, the InBev Baillet-Latour Health Prize in 2011, and the Ilse and Helmut Wachter Foundation Award and the Milstein Award in 2012.
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