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Heads of Laboratories

Head shot of Jean-Laurent Casanova
Jean-Laurent Casanova, M.D., Ph.D.
Investigator, Howard Hughes Medical Institute
Professor
Senior Attending Physician
St. Giles Laboratory of Human Genetics of Infectious Diseases
Jean-Laurent.Casanova@rockefeller.edu

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.



EDUCATION

M.Sc., 1987
Ph.D. in biology, 1992
Paris Pierre et Marie Curie University

M.D., 1995
Paris Descartes University

 

MEDICAL TRAINING

Residency in pediatrics, 1992–1995

Clinical and Research Fellow in pediatric hematology and immunology, 1996–1999

Assistance Publique-Hôpitaux de Paris

POSITIONS

Investigator, 1996–1999
Professor, 1999–2008
Visiting Professor, 2008–
Necker Hospital and School of Medicine, Paris Descartes University

Senior Attending Pediatrician, 1999–2008
Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris

Professor, 2008–
The Rockefeller University

Senior Attending Physician, 2008–
The Rockefeller University Hospital

International Research Scholar, 2005–2008
Investigator, 2014–
Howard Hughes Medical Institute

AWARDS

Professor Lucien Dautrebande Pathophysiology Foundation Prize, 2004

Richard Lounsbery Award, 2008

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

Stanley J. Korsmeyer Award, American Society for Clinical Investigation, 2016

Inserm Grand Prix, 2016

Distinguished Service Award, Clinical Immunology Society, 2018

MEMBERSHIPS

Foreign Associate, National Academy of Sciences
International Member, National Academy of Medicine
Member, European Molecular Biology Organization

SELECTED PUBLICATIONS

Zhang, S.Y. et al. Inborn errors of RNA lariat metabolism in humans with brainstem viral infection. Cell 172, 952–965 (2018).

Israel, L. et al. Human adaptive immunity rescues an inborn error of innate immunity. Cell 168, 789–800 (2017).

Okada, S. et al. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science 349, 606–613 (2015).

Zhang, X. et al. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. Nature 517, 89–93 (2015).

Ciancanelli, M.J. et al. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science 348, 448–453 (2015).


Dr. Casanova is a faculty member in the David Rockefeller Graduate Program and the Tri-Institutional M.D.-Ph.D. Program.