Antibiotics have played a crucial role in saving the lives of many TB patients, yet a significant disparity exists between the high prevalence of tuberculosis infection and the actual severity of the disease. Tuberculosis (TB), a complex and challenging condition, remains the leading cause of death from infectious diseases worldwide. Despite this, it’s estimated that only about 5% of Mycobacterium tuberculosis (Mtb) infections lead to fatalities. While antibiotics are undeniably effective, the gap between infection rates and disease outcomes remains. New research points to genetic susceptibility as a potential explanation for this disparity.
Researchers at The Rockefeller University have identified a rare mutation that significantly increases the likelihood of developing tuberculosis in its carriers, without increasing their risk for other infectious diseases. This discovery, recently published in Nature, has the potential to challenge and reshape long-standing views about the immune system.
It has long been established that an acquired deficiency of the pro-inflammatory cytokine TNF is associated with a heightened risk of developing TB. In the latest study, led by Stephanie Boisson-Dupuis and Jean-Laurent Casanova at Rockefeller University, researchers uncovered a genetic cause of TNF deficiency and its underlying mechanism. They found that a lack of TNF disrupts a specific immune response in the lungs, resulting in severe—but surprisingly targeted—illness.
The findings suggest that TNF, traditionally seen as a central player in the immune response, might actually have a more limited role—specifically in protecting the lungs against TB. This discovery could have significant clinical implications.
“For the past 40 years, scientific literature has credited TNF with a broad range of pro-inflammatory functions,” says Jean-Laurent Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases. “However, beyond its role in defending the lungs against TB, TNF may have a much narrower impact on inflammation and immunity.
Casanova’s lab has spent over two decades investigating the genetic causes of TB, conducting fieldwork in multiple countries and collaborating with physicians worldwide. Their efforts have led to the creation of a vast and continuously expanding database of whole-exome sequences from a global pool of patients—totaling more than 25,000 individuals to date, with approximately 2,000 of them having had TB.
Over the years, Casanova’s lab has identified several rare genetic mutations that increase vulnerability to TB. One example is mutations in the CYBB gene, which disrupt an immune mechanism known as the respiratory burst, crucial for producing reactive oxygen species (ROS). Despite its name, the respiratory burst occurs within immune cells throughout the body, not just in the lungs.
ROS are vital for enabling phagocytes—white blood cells that “consume” pathogens—to destroy the invaders they engulf. When ROS production is compromised, these pathogens can thrive unchecked, leading to severe complications. As a result, individuals with the CYBB mutation become susceptible not only to TB but also to a wide array of infectious diseases.
In their current study, the team suspected that a similar inborn error of immunity might be behind the severe, recurrent TB infections observed in two relatives from Colombia—a 28-year-old woman and her 32-year-old cousin—who had been repeatedly hospitalized due to serious lung conditions. Despite initially responding well to anti-TB antibiotics, their illness returned within a year each time.
Intrigued by this recurring pattern, the researchers performed a detailed genetic analysis on both patients. They discovered that both carried a novel mutation in a gene associated with TNF production. This mutation weakened the body’s ability to mount a strong immune response in the lungs, allowing TB to persist and recur despite treatment. This finding underscores the critical role of genetic factors in TB susceptibility and highlights the need for personalized treatment strategies.
The discovery also led the team to investigate whether other patients with recurrent TB might have similar genetic vulnerabilities. By examining their extensive database of whole-exome sequences, they aim to identify additional genetic mutations that contribute to TB susceptibility. Such discoveries could lead to more targeted therapies, ultimately improving outcomes for patients who continue to battle this relentless disease despite standard treatments.
Puzzlingly, the long-term health records of the two patients indicated that their immune systems functioned normally and that they were otherwise healthy.
To understand why they were especially prone to TB, the researchers conducted whole-exome sequencing on both patients and performed a genetic analysis of their parents and relatives.
It was discovered that the two individuals were the only members of their extended family with a mutation in the TNF gene. TNF, short for “tumor necrosis factor,” encodes proteins that play a crucial role in regulating various biological processes. Elevated TNF production is associated with several conditions, including septic shock, cancer, rheumatoid arthritis, and cachexia, a condition marked by severe weight loss.
The TNF protein is primarily secreted by macrophages, a type of phagocyte that depends on ROS molecules generated by the respiratory burst to effectively eliminate pathogens it has ingested.
In these two patients, the malfunctioning TNF gene prevented the respiratory burst and the production of ROS molecules. As a result, their alveolar macrophages in the lungs were overwhelmed by Mycobacterium tuberculosis (Mtb).
“We knew the respiratory burst was vital for defending against various mycobacteria, but we’ve now learned that TNF regulates this process,” says Boisson-Dupuis. “Without TNF in alveolar macrophages, individuals become especially vulnerable to airborne TB.”
She adds, “It’s quite surprising that these patients, although repeatedly exposed to other infectious microbes, have never contracted any other infections. They appear to be uniquely predisposed to TB.”
This finding also clarifies why TNF inhibitors, used for treating autoimmune and inflammatory diseases, increase the risk of TB. The absence of TNF impairs a crucial component of the body’s defense against the disease.
