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TB Research May Transform Inflammatory Disorder Treatments

Tuberculosis (TB) is a complicated deadly bacterial infection. It is the leading cause of death due to any infectious disease in the world. However, only about 5 percent of Mycobacterium tuberculosis infections result in such deaths. While antibiotics have saved millions of lives, a gap between infection rates and the severity of disease persisted. Genetic susceptibility can explain the difference in disease outcomes, said researchers.

An unexpected mutation that puts people at risk for TB-not any other infectious disease has been found by scientists at Rockefeller University. Researchers at Rockefeller University uncovered a surprise mutation that increases the risk of developing TB but not other infectious diseases published in Nature.

Here, Stephanie Boisson-Dupuis and Jean-Laurent Casanova report the genetic etiology of deficiency in a pro-inflammatory cytokine known as TNF. The specific deficiency they described ablates an immunoprotective function that is normally lung-specific, rendering affected individuals susceptible to narrowly targeted severe illness. These data suggest that TNF, typically thought of as performing a general function in immunity, may have a more specialized function. These results could have great clinical significance.

Casanova, the head of the St. Giles Laboratory of Human Genetics of Infectious Diseases, says, “The last 40 years of research have ascribed innumerable pro-inflammatory functions to TNF. But its role, beyond defending the lungs against TB might be very limited in inflammation and immunity.”

Since the early 1990s, Casanova’s lab has researched the genetic causes of TB, working together with clinicians worldwide. They maintain a database of whole-exome sequences from more than 25,000 patients, including approximately 2,000 with TB. Using the database, the team has identified several rare genetic mutations that put a person at risk for developing TB. For instance, different mutations in the CYBB gene disrupt the respiratory burst defense mechanism that produces ROS, which is pathogen-degrading. Without the ROS, these pathogens survive and cause a host of infectious diseases.

In the current study, two Colombian patients who had very severe and recurrent TB were studied. These patients responded to anti-TB antibiotics initially. However, the infection recurred within a year. Otherwise, their immune systems were normal. The researchers did whole-exome sequencing of the patients and their relatives.

Through their analysis, the exact mutation shared between the two patients was identified; it was a mutation affecting a gene involved in several biological processes. Diseases associated with the overproduction of TNF include septic shock, cancer, and rheumatoid arthritis. Macrophages produce the protein. To kill the pathogen, they need ROS. However, in these two patients, the inactive gene prevents ROS production. Thus, the Mtb overpowered their alveolar macrophages.

We knew the respiratory burst was important for mycobacteria protection, but now we can see that TNF controls this. Without TNF, alveolar macrophages allow the spread of airborne TB,” Boisson-Dupuis says.

This study also explains why TNF inhibitors used to treat autoimmune. And inflammatory diseases can carry an added risk of TB. Without TNF, a critical defense against TB is lost.

These observations may point to a reassessment of the function of TNF in immunity and possibly to new therapeutic avenues. As Casanova remarks, “While TNF is indispensable for immunity against Mtb. It is redundant for most if not all other pathogens. We now have to investigate which other cytokines are taking over TNF’s functions. And may become alternative targets to treat inflammatory diseases.”

ANI

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