Published on 26.11.2019
Proving the genetic origins of infectious diseases is the leitmotif that has driven Jean-Laurent Casanova’s* research team since its creation over 20 years ago. From the time she finished her degree and from her first meeting with the doctor-researcher, Emmanuelle Jouanguy—today Inserm’s research director at Imagine Institute—was inspired by Casanova’s dynamism and the clarity of his scientific vision. Because, at the time, no evidence supported his theory. Since that time, evidence has accumulated and Emmanuelle Jouanguy has helped to identify genes that cause an extreme sensitivity to a specific bacteria or virus when they malfunction.
Research, a clear choice
Even though the world of research had attracted Emmanuelle Jouanguy since high school, she chose to first complete a BTS (two-year advanced technical degree) in biological analysis in order to secure employment, before returning to University to complete her bachelor’s degree. It was during this period that she met Jean-Laurent Casanova, a young doctor who had just finished his PhD in science, and they began a collaboration that has now lasted 26 years. “I immediately felt that I would learn a lot, but also that it would push me to reach my full potential,” remembers the researcher. After spending several months on a basic research project, her work soon became focused on a rare syndrome: mendelian susceptibility to mycobacterial disease (MSMD). “It all started with a question, explains the researcher. We wanted to know why some children develop an abnormal susceptibility to mycobacteria when it isn’t very virulent for the rest of the population, like the BCG vaccine for example.” With no obvious signs of the slightest immunodeficiency, children die after a single BCG vaccination.
“Based on the literature, a certain number of immunity genes seemed to be good contenders for being responsible for this pathology, continues Emmanuelle Jouanguy. We therefore focused our research on these genes. Our intuition was correct because we were able to prove that a mutation in the interferon yR1 encoding gene was to blame.”
The results continued to come, exposing more and more infections that develop in genetically predisposed patients. It is almost as if certain patients’ makeup encourages certain infections. “We were the first to describe infectious diseases as also being genetic diseases, which opened up a new path for helping families and patients,” explains Emmanuelle Jouanguy.
From bacteria to viruses
Upon finishing her PhD, Emmanuelle Jouanguy left to do her post-doc in Strasbourg in the laboratory of Jules Hoffman, a specialist in immunity in drosophilae, who was awarded the Nobel Prize in Medicine in 2011. There, she dedicated herself to developing a model study on antiviral response in this fly, a highly useful model for understanding the underlying biological mechanisms.
Upon returning to Jean-Laurent Casanova’s newly-created laboratory, the young researcher took advantage of her knowledge on viruses to find out if certain genetic makeups can favor associated severe clinical forms of viruses. “In the case of Herpes simplex virus 1 (HSV1) infections, benign forms result in a cold sore. Some people will develop invasive forms, whether cerebral or hepatic. We showed that in children who are carriers of a genetic defect affecting the type I TLR3-IFN pathway, viral replication is no longer controlled in the brain, which results in herpes simple encephalitis, a very severe brain disorder.” Following this first “viral” project, Emmanuelle Jouanguy became worked on other viral infections, such as epidermodysplasia verruciformis, a rare disease related to certain human papillomaviruses (HPVs) in close collaboration with Prof. Gérard Orth, a pioneer in the discovery of HPVs, or viral fulminant hepatitis.
“Research is built on communication, collaboration and exchange”
Since then, the laboratory has found that other viral infections, and particularly the flu, can be a much more aggressive in some patients due to a genetic predisposition. “This was proof that viral infections can also be genetic diseases, explains Emmanuelle Jouanguy. All these discoveries are the result of great teamwork. Research is built on communication, collaboration and exchange, which help us to refine the way we see things, to understand the question being asked.”
Now, Emmanuelle Jouanguy has embarked on a new challenge: better understanding the immune responses of different tissues to the same virus. “There are viruses with specific tissue tropisms, like the hepatitis A virus which only infects the liver, for example, whereas herpes (HSV1) can have clinical manifestations in several tissues (brain, liver, or skin), she points out. In the case of HSV1 infections, the genetic defects that we have identified only explain the infection’s severity in the brain, not in the liver or skin. The nature of the immune response which occurs during a viral infection is therefore not only related to the virus, but seemingly also to the tissue affected.” A new piece of the immunity puzzle to decipher.
*Today, Jean-Laurent Casanova is a professor at Paris Descartes University/Necker-Enfants Malades Hospital (AP-HP), and a professor at Rockefeller University/Howard Hughes Medical Institute in New York. Along with Laurent Abel, he is founder of the Human Genetics of Infectious Diseases Laboratory, an Inserm international laboratory with two branches, one at Rockefeller University in New York, and the other at Imagine Institute at Necker, in Paris.