The unsuspected role of PD-1 molecule in mycobacterial infections

With 1.4 million deaths and 10 million new cases each year, tuberculosis (TB) is one of the top ten causes of death in the world according to the World Health Organization. This infectious disease is transmitted through the air by a mycobacterium called Mycobacterium tuberculosis, better known as Koch's bacillus. It attacks primarily the lungs, but can spread to other organs, causing fever, chronic cough, shortness of breath, chest pain, fatigue and loss of appetite. A quarter of the world's population is infected with this mycobacterium, but only 5% to 10% develop the symptoms of TB.

This discrepancy can be explained by different genetic susceptibility among individuals, increasing the risk of developing the disease in some. “This is our hypothesis”, says Stéphanie Boisson-Dupuis (*), a geneticist at the New York branch of the Laboratory of Human Genetics of Infectious Diseases headed by Prof. Jean-Laurent Casanova and Laurent Abel (**). “The goal of our research is to show that tuberculosis, in addition to being an infectious disease, is also a genetic disease”.

The key role of gamma interferon

This idea is supported by an ever-growing body of evidence. In 2018, Prof. Jean-Laurent Casanova's team had thus identified a common genetic variant that - when present on both copies of the TYK2 gene - explains 1% of TB cases in Europe. “This variant is the first common monogenic cause identified for tuberculosis. It causes a defect in the production of interferon gamma, which is a key player in anti-mycobacterial immunity”, adds the geneticist. Other rare variants have also been identified in recent years. All are associated with a defect in the production of or response to interferon gamma.

On June 28, 2021, a new study published in the journal Nature Medicine adds a stone to this scientific edifice in favor of a genetic origin of tuberculosis. Researchers at Imagine and Rockefeller University have identified a new variant in a patient that is present on both copies of the PDCD1 gene that encodes the PD-1 protein. "We have shown that this variant leads to a complete absence of PD-1 on the surface of cells, which at the molecular and cellular level, leads to a defect in the production of interferon gamma that increases the risk of developing tuberculosis," explains Stéphanie Boisson-Dupuis.

When immunotherapy reactivates a latent infection

This protein is well-known. It is the main target of immunotherapies, the new flagship treatments against cancer. Its presence on the surface of our cells is like a banner signaling to immune cells - in particular T cells - that they belong to the same camp. As a result, our cells are recognized as belonging to the "self" and spared. However, some cancers use this inhibiting mechanism to slip through the cracks. Immunotherapy consists of removing this inhibition by using anti-PD1 antibodies, thus letting the immune cells "kill" the cancer cells.

“However, the medical literature reports cases of patients who, when treated with anti-PD1 drugs for their cancer, reactivate a latent Mycobacterium tuberculosis infection and develop tuberculosis" warns Stéphanie Boisson-Dupuis. “It is therefore important to test patients prior to their immunotherapy, to check if they are infected or not. This allows physicians to anticipate and implement appropriate patient management.”