Johns Hopkins Medicine researchers have discovered that navitoclax, an experimental drug currently in cancer clinical trials, could significantly enhance tuberculosis treatment by helping infected cells undergo controlled death rather than destructive inflammation. The study, published March 27 in Nature Communications and funded by the National Institutes of Health, demonstrates promising results in mouse models that could lead to shorter, more effective TB therapies.
Addressing a Global Health Crisis
Tuberculosis has likely become the leading cause of death globally again, with an estimated 1.25 million deaths and 10.8 million new cases in 2023, according to the World Health Organization. Current TB treatment regimens are lengthy, expensive, and leave patients vulnerable to relapse and lung scarring, with hundreds of thousands of infections resistant to gold-standard antibiotic treatments.
"Current treatment regimens for TB are lengthy, expensive and leave patients vulnerable to relapse and lung scarring. Our research shows that adding in a host-directed therapy has extraordinary promise to solve these problems," said Dr. Sanjay Jain, the study's senior author and pediatric infectious diseases specialist at Johns Hopkins Children's Center.
Understanding TB's Cellular Hijacking Mechanism
The research reveals how Mycobacterium tuberculosis, the bacterium causing TB, manipulates infected lung cells to survive and spread. In early infection stages, lung cells naturally limit bacterial spread through apoptosis, a controlled cell death process. However, as TB progresses, the bacterium shifts the balance toward necrosis, an uncontrolled cell death that causes widespread inflammation and tissue damage.
Dr. Medha Singh, the study's first author and pediatric infectious diseases fellow, explains that the TB bacterium accomplishes this by prompting infected host cells to produce Bcl-2, a family of anti-apoptotic proteins. This molecular hijacking creates necrotic niches within the lung that prevent immune system attacks and allow bacteria to multiply.
Breakthrough Combination Therapy Results
The researchers tested navitoclax, a Bcl-2 inhibitor, alongside standard TB antibiotics rifampin, isoniazid, and pyrazinamide (RHZ) in mice infected with M. tuberculosis. The results demonstrated significant improvements over standard treatment alone.
Mice receiving the combination therapy showed a 40% reduction in necrotic lung lesions and reduced likelihood of infection spreading to other organs like the spleen over four weeks of treatment. Using clinically translatable positron emission tomography (PET) imaging, the team found that navitoclax doubled pulmonary apoptosis and reduced lung scarring by 40% compared to standard TB treatments alone.
Most remarkably, animals receiving navitoclax with RHZ decreased their bacterial burden 16 times more effectively than those receiving standard treatment alone, despite navitoclax having no direct effect on M. tuberculosis bacteria.
Clinical Translation Potential
Dr. Laurence Carroll, study author and assistant professor of radiology, notes that the imaging technologies used in the study are clinically translatable, potentially allowing for early readouts of host-directed therapy effectiveness in human trials.
The findings suggest navitoclax could offer benefits not only for TB patients but also for those with other chronic bacterial infections, including Staphylococcus aureus and non-TB mycobacteria highly prevalent in the United States. However, clinical trials would be needed to validate these effects in humans.
Future Treatment Implications
If successful in clinical trials, doctors might eventually add navitoclax or similar drugs to standard antibiotic regimens. This approach could potentially shorten the typical daily six-month course of TB treatment, reduce lung scarring incidence or post-TB lung disease, and improve outcomes for patients with drug-resistant TB.
The research represents a significant advance in host-directed therapy approaches, targeting infected host cells rather than the bacteria directly. This strategy addresses the growing challenge of antibiotic resistance while potentially reducing the long-term complications that affect tens of millions of TB survivors worldwide.
