New findings on tuberculosis could change the way we treat inflammatory diseases

Tuberculosis (TB) is a daunting scourge. It is the leading cause of death from infectious disease worldwide, yet these deaths are estimated to account for approximately 5% of Mycobacterium tuberculosis (Mtb) infections. Antibiotics may have saved the lives of some people with Mtb, but a gap persists between the prevalence of infection and the targeted severity of its impact. A growing body of evidence suggests that genetic vulnerabilities to TB explain this discrepancy.

Researchers at Rockefeller University have discovered another rare mutation that significantly increases the risk of tuberculosis in carriers, but curiously, not other infectious diseases. The discovery, recently published in Naturecould upend long-held assumptions about the immune system.

It has long been known that an acquired deficiency of a pro-inflammatory cytokine called TNF is linked to an increased risk of developing tuberculosis. The current study, led by Rockefeller’s Stephanie Boisson-Dupuis and Jean-Laurent Casanova, has revealed a genetic cause of TNF deficiency, as well as the underlying mechanism: A lack of TNF inhibits a specific immune process in the lungs, leading to a severe but surprisingly targeted disease.

These results suggest that TNF, long considered a key galvanizer of the immune response, may actually play a much more limited role – a finding with far-reaching clinical implications.

“Over the past 40 years, the scientific literature has attributed a wide variety of pro-inflammatory functions to TNF,” says Casanova, director of the Human Genetics of Infectious Diseases Laboratory at St. Giles. “But beyond protecting the lungs from 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 large network of collaborating physicians around the world. They maintain a constantly growing database of whole-exome sequences from a global pool of patients, more than 25,000 people to date. Of these, about 2,000 have had tuberculosis.

Over the years, they have identified several rare genetic mutations that make some people vulnerable to TB. For example, mutations in a gene called CYBB 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-eating white blood cells, called phagocytes (from the Greek for “eat”), destroy the invaders they have devoured. If ROS are not produced, these pathogens can proliferate unchecked, leading to debilitating complications. As a result, carriers of this CYBB mutation become vulnerable not only to tuberculosis, but to a wide variety of infectious diseases.

In the current study, the team suspected that a similar innate immune error 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 hospitalized multiple times with severe lung problems. Each round, they initially responded well to TB antibiotics, but after a year, they became ill again.

Interestingly, their long-term medical records showed that their immune systems were functioning normally and they were otherwise healthy.

A revealing deficiency

To find out why they were particularly susceptible to tuberculosis, the researchers performed whole-exome sequencing on both individuals, as well as genetic analysis of their respective parents and relatives.

The two men were the only members of their extended family to have a mutation in the TNF gene, which codes for proteins linked to the regulation of various biological processes. Short for “tumor necrosis factor,” increased production of TNF 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 clear out pathogens they have consumed.

In both patients, the TNF gene failed to function, 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 drive was important to protect people against various types of mycobacteria, but now we know that TNF actually regulates the process,” Boisson-Dupuis says. “And when it’s absent from alveolar macrophages, people are susceptible to airborne TB.”

She adds: “It is very surprising that the people we studied are adults who have never had other infectious diseases, even though they have been repeatedly exposed to their microbes. They apparently have a selective risk of tuberculosis.”

Treatment potential

The discovery also solves a long-standing mystery about why TNF inhibitors, used to treat autoimmune and inflammatory diseases, increase the risk of contracting tuberculosis. Without TNF, a key part of the defense against this disease is ineffective.

These results could lead to a radical reevaluation of the role of TNF in immune function and to new treatment possibilities.

“TNF is necessary for immunity to Mtb, but it appears to be redundant for immunity to many other pathogens,” Casanova says. “So the question is, what other pro-inflammatory cytokines are doing the job we thought TNF was doing? If we can figure that out, we may be able to block those cytokines instead of TNF to treat diseases in which inflammation plays a role.”