San Francisco, California
London, United Kingdom
Affiliation: The Rockefeller University
Professional Title(s): Investigator, Howard Hughes Medical Institute; Senior Attending Physician, The Rockefeller University Hospital; Professor, St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University
Talk Title: Toward a genetic theory of childhood infectious diseases
Abstract: The hypothesis that inborn errors of immunity underlie infectious diseases is gaining experimental support. However, the apparent modes of inheritance of predisposition or resistance differ considerably between diseases and between studies. A coherent genetic architecture of infectious diseases is lacking. We suggest here that life-threatening infectious diseases in childhood, occurring in the course of primary infection, result mostly from individually rare but collectively diverse single-gene variations of variable clinical penetrance, whereas the genetic component of predisposition to secondary or reactivation infections in adults is more complex. This model is consistent with (i) the high incidence of most infectious diseases in early childhood, followed by a steady decline, (ii) theoretical modeling of the impact of monogenic or polygenic predisposition on the incidence distribution of infectious diseases before reproductive age, (iii) available molecular evidence from both monogenic and complex genetics of infectious diseases in children and adults, (iv) current knowledge of immunity to primary and secondary or latent infections, (v) the state of the art in the clinical genetics of non-infectious pediatric and adult diseases, and (vi) evolutionary data for the genes underlying single-gene and complex disease risk. With the recent advent of new-generation deep resequencing, this model of single-gene variations underlying severe pediatric infectious diseases is experimentally testable.
Biography: Jean-Laurent Casanova, MD, PhD, received his medical degree from the Université Paris Descartes in 1987. After receiving training at the Pasteur Institute in Paris and the Ludwig Institute for Cancer Research in Lausanne, Switzerland, he received his Ph.D. in Immunology from the Université Pierre et Marie Curie in 1992. Following a residency in pediatrics, he completed a clinical fellowship in the pediatric immunology-hematology unit of the Necker Medical School in Paris. In 1999, he was appointed a professor of pediatrics at Necker, where, with Dr. Laurent Abel, he cofounded and codirected the Laboratory of Human Genetics of Infectious Diseases. In 2008, he was appointed a professor at The Rockefeller University in New York City.
Dr. Casanova is a physician-scientist who studies the genetics of human predisposition to pediatric infectious diseases, particularly mycobacterial diseases, invasive pneumococcal diseases, and herpes simplex encephalitis. He is interested in identifying Mendelian “holes” in the immune defense of otherwise healthy children who are susceptible to specific infectious diseases, work that has resulted in a paradigm shift in human clinical medicine and fundamental immunology.
Since the 1950s until recently, it was believed that mutations in a single gene confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections have been associated with the inheritance of multiple susceptibility genes (multiple genes, one infection). Dr. Casanova and Dr. Abel identified and characterized a new group of genes that predispose otherwise healthy individuals to a single type of infection (one gene, one infection), a novel causal relationship that modified the paradigm that had dominated the field for decades.
Dr. Casanova’s team has identified impaired signaling pathways associated with 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-STAT-1 pathway), invasive pneumococcal disease (mutations of the TLR-IRAK4-MyD88-NF-κB pathway) and herpes simplex encephalitis (mutations of the TLR3-UNC93B1-IFN-α/β pathway). 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 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 to complex predisposition in adults. The laboratory is now principally focused on testing the hypothesis that life-threatening infectious diseases of childhood result from collections of rare single-gene inborn errors of immunity.
Dr. Casanova was an international research scholar with the Howard Hughes Medical Institute from 2005 to 2008. He is a member of the European Molecular Biology Organization and the American Society for Clinical Investigation. He was the recipient of the Professor Lucien Dautrebande Pathophysiology Foundation Prize from the Belgian Royal Academy of Medicine in 2004, and the Richard Lounsbery Award from the French and American Academies of Sciences in 2008. In 2009, he received a doctorate honoris causa from the University of Zürich, and the Oswald Avery Award from the Infectious Diseases Society of America. In 2010, he was awarded the E. Mead Johnson Award from the Society for Pediatric Research, and a doctorate honoris causa from the University of Debrecen. He is a member of the National Academy of Medicine as well as the National Academy of Sciences.
To read more about Jean-Laurent Casanova’s research, please visit: Google Scholar – Jean-Laurent Casanova
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