According to Johns Hopkins Medical researchers, cancer treatments currently in clinical trials could enhance tuberculosis treatment by triggering a more controlled process of cell death, potentially reducing lung damage in survivors.
The study found that when the experimental drug Navitoclax added it to standard tuberculosis (TB) treatment, it helped infected cells die through a controlled process called apoptosis rather than the more destructive necrosis that usually occurs in TB infection.
“Current tuberculosis treatment options are lengthy and expensive, leaving patients vulnerable to relapse and lung scarring. Our study shows that coupled with host-guided treatments can address these issues.”
The discovery, published on March 27 in Nature Communications, could lead to more effective treatments to reduce the severity of post-TB lung disease that affects millions of tuberculosis survivors around the world.
Although preventable and treatable, tuberculosis may still restore its status as the world’s deadliest infectious disease, with an estimated 1.25 million deaths and 10.8 million new cases in 2023, according to the World Health Organization. Thousands of these infections resist standard antibiotics.
When Mycobacterium tuberculosis (the bacteria responsible for tuberculosis) infects lung cells, it manipulates the cell death pathway. In the early stage of infection, infected cells often experience apoptosis – a regulated, damaged form of cell death. However, as infection develops, bacteria trigger necrosis, an uncontrolled cell death that causes inflammation and damages surrounding tissue.
“While apoptosis can be compared with controlled demolition of a controlled building, necrosis is more like bomb damage,” Jain explained.
Tuberculosis bacteria achieve this by prompting infected cells to produce the anti-apoptotic protein family Bcl-2. “The hijacking of this usually healthy molecular pathway has a significant advantage for M. tuberculosis,” said Medha Singh, the first author of the study and a pediatric infectious disease researcher at the School of Medicine. It creates “small necrotic fissures in the lungs to prevent the onset of the immune system and allow bacteria to multiply.”
To test whether inhibiting BCL-2 can improve tuberculosis treatment outcomes, the researchers treated mice with Mycobacterium tuberculosis using standard tuberculosis antibiotics (rifampin, isoniazid and pyrazinamide). Some mice also received Navitoclax, a BCL-2 inhibitor currently in clinical trials in cancer.
Four weeks later, mice receiving standard antibiotics and NAVITOCLAX showed significant improvement compared to antibiotics alone. Their necrotizing lung lesions have been reduced by 40%, and infection is unlikely to spread to other organs such as the spleen. Combination treatment also reduced lung scar by 40%.
Imaging studies using positron emission tomography (PET) show that the addition of Navitoclax doubled the amount of pulmonary apoptosis. Although Navitoclax had no direct effect on Mycobacterium tuberculosis when used alone, animals receiving the drug and antibiotics were 16 times less effective than animals receiving only standard treatment.
These results suggest that Navitoclax may offer similar benefits to patients with tuberculosis and other chronic bacterial infections, such as Staphylococcus aureus and non-TB mycobacteria,
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