Immunology, Medicine and Translational Research
The Rockefeller University
Dr. Casanova is also a professor, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases, and senior attending physician at the Rockefeller University, and a visiting professor at the Necker Hospital for Sick Children, Paris Descartes University. He was an HHMI international research scholar from 2005 to 2008.
Jean-Laurent Casanova studies the human genetic determinism of childhood infectious diseases. He has identified single-gene inborn errors of immunity underlying diseases caused by specific pathogens. His discoveries include the molecular genetic basis of mycobacterial diseases (inborn errors of IFN-γ immunity), and of other diseases (and their affected genes) such as herpes simplex encephalitis (TLR3), invasive pneumococcal disease (TIR and RPSA), chronic mucocutaneous candidiasis (IL-17), and Kaposi sarcoma (OX40). Pursuing both biological and medical goals, he attempts to establish a genetic theory of childhood infectious diseases.
When he was a clinical fellow at the Necker Hospital in Paris in the mid-1990s, Jean-Laurent Casanova made a discovery that set the stage for his entire career. A handful of healthy children had fallen ill with severe infections after receiving the BCG vaccine, which was supposed to protect them against tuberculosis. The vaccine primes the body's immune defenses by delivering living but usually innocuous relatives of the tuberculosis bacteria. But in certain children, he found, the bacteria from the vaccine had run rampant.
Casanova has been investigating cases like these ever since to understand why some children get sick during the course of an infection while others exposed to the same pathogen do not. "My entire life is dedicated to testing one hypothesis and trying to prove or disprove it," he says. He's been studying whether certain people harbor rare genetic defects that undermine their immune defenses against particular microbes.
Casanova comes from a family that has no physicians or scientists—his father is a philosopher and his mother ran a business. But by age 18 he was certain he wanted to become a physician-scientist who treats patients and performs research. "I felt compelled to do that," he says. Thanks to his dual training, when he noticed the unusual bacterial infections in the BCG recipients, he was prepared to attempt to track down the cause. At the time, researchers thought that defects in individual genes would suppress the immune system, leaving children vulnerable to many illnesses. An example of such a condition is severe combined immunodeficiency (SCID), in which children suffer from infection after infection because they lack microbe-fighting T cells. But several of the children didn't have SCID or any other obvious illness, suggesting that something else was going on.
So Casanova decided to do some sleuthing. To find out if similar cases were showing up elsewhere, he wrote letters to every pediatrician who worked at a public hospital in France—more than 300 doctors. "This was before email," he recalls, so gathering the addresses and sending the letters was a much bigger job than it would be today. But it paid off. Many of the doctors wrote back to report unexplained infections. He and his colleagues calculated that these infections affect about one in every 2 million French children who received the vaccine. And by analyzing the DNA of a girl who had died after receiving the BCG injection, they pinpointed one genetic defect that was responsible. The girl carried a faulty version of a receptor that enables cells to respond to interferon gamma, a molecule essential for combating bacterial invaders.
That was just the beginning for Casanova and his team. "We got results in one patient after another and with one infection after another." Working first at the Necker Hospital, where he was an HHMI international research scholar from 2005 to 2008, and then at the Rockefeller University in New York City, he and his colleagues uncovered the genetic glitches responsible for susceptibility to several kinds of common bacteria, fungi, and viruses. And they've deciphered how some of these flaws impair the immune system. For example, his team has identified additional faulty genes that weaken defenses against mycobacteria, the type of bacteria in the BCG vaccine. The most common of these defects cuts patients' production of interferon gamma, presumably leaving the patients unable to fight off mycobacteria. That result suggests that interferon gamma might help people who become sick after receiving the BCG vaccine, although doctors have tried this treatment on only a few children.
Other successes for his team include identifying genetic flaws that make people vulnerable to severe influenza and herpes simplex encephalitis, a potentially lethal brain condition caused by herpes simplex virus-1, which typically causes only cold sores. Although the mutations the researchers have discovered are rare, they are medically important, Casanova says. "There are a lot of these rare mutations, so collectively they account for a lot of patients." And he thinks that other genetic weaknesses remain to be discovered. "We've only looked at a small proportion of diseases and patients," he says.