Tuberculosis is a baffling scourge. It is the leading cause of death from infectious disease in the world, and yet it is estimated that such deaths account for perhaps 5% of all tuberculosis infections. Mycobacterium tuberculosis (TBM). Antibiotics may be credited with saving the lives of some people with TB, but a gap remains between the prevalence of infection and the severity of its impact. A growing body of evidence suggests that genetic vulnerability to TB explains this gap.
Now, researchers at Rockefeller University have discovered another rare mutation that makes its carriers much more likely to get tuberculosis, but, curiously, not other infectious diseases. This finding, recently published in Naturecould radically change long-held assumptions about the immune system.
It has long been known that acquired deficiency of a pro-inflammatory cytokine called TNF is associated with an increased risk of developing tuberculosis. The current study, led by Stéphanie Boisson-Dupuis and Jean-Laurent Casanova of Rockefeller, revealed a genetic cause of TNF deficiency as well as the underlying mechanism: a lack of TNF incapacitates a specific immune process in the lungs, leading to a severe, but surprisingly targeted disease.
The findings suggest that TNF, long considered a key galvanizer of the immune response, may actually play a much more limited role — a discovery with wide-ranging clinical implications.
“Over the past 40 years, the scientific literature has attributed a wide variety of pro-inflammatory functions to TNF,” said Casanova, director of the Human Genetics of Infectious Diseases Laboratory at St. Giles. “But beyond protecting the lungs against tuberculosis, it may have a limited role in inflammation and immunity.”
Rare risk
Casanova’s lab has been studying the genetic causes of tuberculosis for more than two decades through fieldwork in several countries and a broad network of collaborating physicians around the world. They maintain a constantly growing database of whole exome sequences from a global group of patients: more than 25,000 people to date. Of these, about 2,000 have had tuberculosis.
Over the years, several rare genetic mutations have been identified that make some people vulnerable to tuberculosis. For example, mutations in a gene called CYBER It can turn off an immune mechanism called the respiratory burst, which produces chemicals called reactive oxygen species (ROS). Despite its lung-sounding name, the respiratory burst occurs in immune cells throughout the body.
ROS help pathogen-consuming white blood cells called phagocytes (from the Greek for “to eat”) destroy invaders they have devoured. If ROS are not produced, those pathogens can proliferate unchecked, leading to debilitating complications. As a result, carriers of this disease are left with no symptoms. CYBER The mutations make them vulnerable not only to tuberculosis but to a wide variety of infectious diseases.
For the current study, the team suspected that a similar inborn error of immunity might be behind the severe, recurring TB infections suffered by two people in Colombia — a 28-year-old woman and her 32-year-old cousin — who had been repeatedly hospitalized with significant lung conditions. In each cycle, they initially responded well to anti-TB antibiotics, but within a year they became ill again.
Most surprisingly, however, their long-term health records showed their immune systems were functioning normally and they were otherwise healthy.
A revealing deficiency
To find out why they were particularly prone to tuberculosis, the researchers performed whole-exome sequencing on both, as well as genetic analysis of their respective parents and family members.
The two were the only members of their extended family with a mutation in the Tumor necrosis factor A gene that encodes proteins involved in regulating a variety of biological processes. Increased production of TNF, short for tumor necrosis factor, is also associated with a variety of conditions, including septic shock, cancer, rheumatoid arthritis, and cachexia, which causes dangerous weight loss.
The protein is largely secreted by a type of phagocyte called a macrophage, which relies on ROS molecules generated by the respiratory burst to kill the pathogens it has consumed.
In these two patients, the Tumor necrosis factor The gene did not work, preventing the respiratory burst from occurring and thus the creation of ROS molecules. As a result, the patients’ alveolar macrophages, located in their lungs, were invaded by Mtb.
“We knew that the respiratory burst was important in protecting people against various types of mycobacteria, but now we know that TNF actually regulates the process,” Boisson-Dupuis says. “And when it’s missing in alveolar macrophages, people will be susceptible to airborne tuberculosis.”
He adds: “It is very surprising that the people we studied are adults who have never suffered from other infectious diseases, despite having been repeatedly exposed to their microbes. They appear to be at selective risk of contracting tuberculosis.”
Treatment potential
The discovery also solves a long-standing mystery about why TNF inhibitors, which are used to treat autoimmune and inflammatory diseases, increase the chances of contracting tuberculosis. Without TNF, a key part of the defense against the disease does not work.
The findings may lead to a radical reappraisal of TNF’s role in immune function and to new treatment possibilities. “TNF is necessary for immunity against Mtb, but it appears to be redundant for immunity against many other pathogens,” Casanova says. “So the question is: What other proinflammatory cytokines are doing the functions we thought TNF was doing? If we can figure that out, we may be able to block these cytokines instead of TNF to treat diseases where inflammation plays a role.”