A new genetic disease linked to the X chromosome explains immunity problems in the face of mycobacteria

In a study published in the journal Cell, the Human Genetics of Infectious Diseases research team from Université Paris Cité, Inserm and AP-HP, led by Prof Jean-Laurent Casanova and Dr Laurent Abel at Institut Imagine, has identified rare variants of the MCTS1 gene responsible for susceptibility to mycobacterial diseases such as tuberculosis. This work, which describes a new genetic disease, confirms that interferon-gamma (IFN-gamma), a protein that activates the immune response, is the main player in the immune reaction to this type of infection, and that the JAK2 protein is also required to trigger the immune response in the event of infection by a mycobacterium.a tuberculose.

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Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, is a deadly infectious disease that has claimed at least a billion lives over the past 2,000 years and still claims 1.5 million lives worldwide every year. For 90% of people infected, M. tuberculosis infection is silent or benign. In very rare cases (around 1 in 50,000 people), a failure of the immune response may be revealed by a severe or even fatal infection, following injection of the tuberculosis vaccine (known as the BCG or Bacille de Calmette et Guérin vaccine), which contains an attenuated form of the bacterium.

Jonathan Bohlen, a post-doctoral student under the supervision of Prof Jean-Laurent Casanova*, Dr Qian Zhang** and Dr Jacinta Bustamante***, has been working on identifying the genetic factors in a group of rare genetic diseases predisposing to infections with mycobacteria (such as tuberculosis) and the Bacille de Calmette et Guérin (BCG) vaccine. This group of diseases, known as MSMD (Mendelian Susceptibility to mycobacterial diseases) occurs more frequently in men than in women.

In the course of his research, J. Bohlen identified rare variants of the MCTS1 gene, located on the X chromosome, in several boys with MSMD (particularly with bone damage) from several continents. These mutations in the MCTS1 gene prevent the production of the protein of the same name, which alters the function of ribosomes, the intracellular structures responsible for protein production. In the case of an MCTS1 mutation, as observed in MSMD patients, the dysfunction of the ribosomes affects the manufacture of certain specific proteins, such as the JAK2 protein, which the team identified and detected in lower quantities in these same patients. The role of JAK2 is to activate the synthesis of interferon-gamma (IFN-γ), another protein involved in activating the immune response to mycobacterial infections, so patients with a mutation in the MCTS1 gene are more susceptible to infections of this type.

Thus, MCTS1 deficiency has a negative impact on IFN-γ production, resulting in a reduced immune response to mycobacterial infection, such as tuberculosis, in these patients. This work therefore provides a better understanding of the mechanisms between mutations in the MCTS1 gene and the anti-mycobacterial immune response.

Remarkably, a genome-wide genetic approach has shed light on the mechanisms of immune response to mycobacterial infection, including the role of IFN-γ as an anti-mycobacterial immune factor. Overall, this study reveals a surprising mechanistic link between the deficiency of a general biochemical mechanism and a selective predisposition to mycobacterial infections. This work marks a new diagnostic and therapeutic advance for this group of infectious diseases, with the identification of a new genetic factor predisposing to mycobacterial infections.



*Prof. Jean-Laurent Casanova: PU-PH, Université Paris Cité and Rockefeller University, Institut Imagine, Hôpital Necker Enfants Malades, AP-HP, co-founder of the Human Genetics of Infectious Diseases Laboratory.

** Dr Qian Zhang: Inserm CR, Institut Imagine, Rockefeller University

*** Dr Jacinta Bustamante : MCU-PH, Université Paris Cité, team leader-Institut Imagine, Centre d'Etudes de Déficits Immunitaires, Hôpital Necker Enfants Malades, AP-HP