highlighting a key player in our defense system ⋅ Inserm, La science pour la santé

A new gene involved in immune response to infections by mycobacteria has been identified by a team Inserm from the Imagine Institute in Paris. It codes for the protein IRF1, a partner of interferon g which plays a major role in the defense system against these infectious agents.

The Inserm laboratory of Jean-Laurent Casanova and Laurent Abel, at the Imagine Institute in Paris, specializes in the study of genetic factors associated with infectious diseases. Within this team, Jacinta Bustamante’s group is particularly interested in individual sensitivity to mycobacteria, the family to which Mycobacterium tuberculosis, responsible for tuberculosis. This infection led to the death of almost 1.5 million people worldwide in 2020, placing the disease in 2e rank of infectious causes of death that year, behind Covid-19…

Twenty genes involved in vulnerability to mycobacterial infections have already been identified in the laboratory. All have a link with interferon g, whether it is related to its production or its interactions with other molecules. So it is considered a key piece of immunity against these particular infectious agents. But the mutations found in these twenty genes only explain half of the cases of severe infections with mycobacteria. To go further, Jacinta Bustamante and her research group have set up an international cohort which currently numbers 1,500 patients with disseminated mycobacterial infections. ” Usually these pathogens remain confined to one organ, for example the lungs in the case of tuberculosis, but if the infection is not controlled, the bacteria can invade other organs, hence the term disseminated,” explains the researcher.

The role of macrophages

Within this cohort, two young patients aged 7-8 with no family ties − one Turkish, the other Argentinian − were chosen because they presented with the same disease. Following their BCG vaccination, the two girls developed a disseminated infection involving the attenuated strain of Mycobacterium bovis used in this vaccine designed to protect against tuberculosis. In addition, they were repeatedly contaminated by Mycobacterium avium, another mycobacterium that caused lymph node disease in both girls. The team studied their genome looking for genetic peculiarities.

This work led to the discovery of two mutations in the gene coding for IRF1. ” This is the first time that we have demonstrated abnormalities in this gene in mycobacterial diseases “, insists Jérémie Rosain, first author of this work. The team studied the functional consequences of these mutations ex vivo, by exposing the different types of immune system cells to mycobacteria. ” We find that in all cell types, the inactivity of IRF1 leads to disturbances in the expression of certain genes and reduces the production of interferon g by a feedback mechanism. But it is in the macrophages that the consequences are particularly important. Indeed, this is where mycobacteria nest and reproducehe says. When the gene coding for IRF1 is mutated, the infection is absolutely not controlled there and the bacteria multiply significantly. The signaling pathways that usually neutralize the infectious agent are simply not activated. In contrast, antiviral immunity is not affected.

Clinical applications

In addition to improving knowledge of mycobacterial diseases, this work marks a diagnostic and therapeutic advance. ” By administering high doses of interferon g in addition to antibiotic therapy, we partially compensate for the absence of functional IRF1 and hope slightly improve infection control in one of the two girls, for whom antibiotics alone are not enoughexplains Jacinta Bustamante. This discovery also encourages the search for mutations in this gene in other people with tuberculosis in order to possibly administer the same treatment to them.. However, to date, such mutations have not been found in other patients in the cohort studied.

Jacinta Bustamante and Jérémie Rosain work in theHuman genetics of infectious diseases team: Mendelian predisposition