Tuberculosis: towards future biomarkers to assess contagiousness

Tuberculosis is a disease that most often affects the lungs, and is caused by the bacteria Mycobacterium tuberculosis. This inflammatory disease, which has affected humans for thousands of years, is not a thing of the past and is still very present throughout the world, causing the death of 1.3 million people in 2022. The progression of the disease is very complicated to follow and the tests do not make it possible to differentiate an active (contagious) form of tuberculosis from a latent (non-contagious) form. However, almost 1/3 of the world’s population is latently infected with the bacteria. Cases of latent infection, without any clinical signs, are the most numerous. Thus, a major challenge is to detect individuals who risk transmitting bacteria to others.

It is in this context that scientists from INRAE ​​and Inserm, in collaboration with researchers from Brazil and Belgium, became interested in neutrophils, a type of white blood cell that kills pathogens using a toxic arsenal. But their massive concentration in sites of infection can destroy tissues, for tuberculosis, the lung in most cases.

The research team discovered two subtypes of neutrophils that have opposing roles in the inflammation process following infection with M. tuberculosis. They identified, on the one hand, conventional neutrophils, which act as an accelerator of inflammation, by producing the pro-inflammatory cytokine called IL-1b. And on the other hand, they showed the role of regulatory neutrophils which act as a brake via the PD-L1 protein, making it possible to block the proliferation of pro-inflammatory T lymphocytes. In this way, this subtype of neutrophils helps to moderate the immune response to avoid destruction of the lung. Researchers have shown that injecting regulatory neutrophils into mice that are highly sensitive to M. tuberculosis had the effect of reducing their lung damage. These observations thus highlight the dangers associated with the prescription of anti-PD-L1 in certain anti-cancer therapies for patients with latent tuberculosis. Indeed, this treatment, which may be indicated to relieve the inactivation of the immune system caused by cancer cells, could reactivate tuberculosis infection by blocking the action of PD-L1.

Furthermore, the researchers showed that the most virulent strains of this bacteria were capable of countering the activity of regulatory neutrophils by inhibiting the production of PD-L1, and thus establishing an inflammatory environment for their own benefit.

These results open perspectives for a diagnosis of the different clinical states of patients, from the transition from the asymptomatic latent form to active, depending on the concentration of classic and regulatory neutrophils in the blood. Indeed, the detection of neutrophil subtypes as biomarkers would then make it possible to target the prescription of antibiotics to individuals who are at risk of developing a contagious form. To test the feasibility of this detection, the researchers will continue their work in collaboration with clinicians.