Tuberculosis is a global health concern, responsible for a significant number of deaths each year due to infections caused by Mycobacterium tuberculosis. Despite the availability of antibiotics to treat this disease, the prevalence of TB remains high, indicating a gap between the number of infections and the impact of the disease. Recent research from The Rockefeller University has identified a rare genetic mutation that increases the susceptibility of individuals to develop TB, without affecting their vulnerability to other infectious diseases. This discovery challenges conventional understandings of the immune system and highlights the importance of genetic vulnerabilities in determining the severity of TB infections.
The study led by researchers Stéphanie Boisson-Dupuis and Jean-Laurent Casanova focused on a genetic mutation that results in a deficiency of a pro-inflammatory cytokine called TNF. This deficiency leads to a specific immune process in the lungs being compromised, resulting in severe illness caused by TB. The findings suggest that TNF, previously thought to have a broad role in immune response, may actually have a more limited function, mainly related to protecting the lungs against TB. This discovery could have important clinical implications for the understanding and treatment of TB.
Casanova’s lab has been conducting research on the genetic causes of TB for over two decades, collaborating with physicians from around the world and compiling a database of whole-exome sequences from thousands of patients with TB. Through their research, they have identified rare genetic mutations that predispose individuals to TB, such as mutations in the CYBB gene that affect immune mechanisms related to the respiratory burst. Mutations in the TNF gene, as identified in the current study, are associated with increased susceptibility to TB due to impaired production of reactive oxygen species in phagocytes, critical for eliminating pathogens.
The study focused on two individuals in Colombia who experienced severe and recurring TB infections, despite having functioning immune systems and being otherwise healthy. Whole-exome sequencing revealed that these individuals had a mutation in the TNF gene, leading to a lack of TNF production and compromised respiratory burst mechanism in their alveolar macrophages. This allowed the Mtb to thrive in their lungs, making them highly susceptible to airborne TB. These individuals did not exhibit increased susceptibility to other infectious diseases, highlighting the specificity of the genetic vulnerability to TB.
The discovery of the role of TNF in protecting against TB offers new insights into the mechanisms of immunity and inflammation, with potential implications for the treatment of TB and other diseases. The findings explain why TNF inhibitors, commonly used to treat autoimmune and inflammatory diseases, increase the risk of contracting TB. Understanding the specific role of TNF in immune response may lead to the development of targeted therapies that block other pro-inflammatory cytokines involved in immune function. The research highlights the importance of genetic factors in determining susceptibility to infectious diseases and the potential for personalized treatment strategies based on individual genetic vulnerabilities.