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Research conducted by investigators at Johns Hopkins Medicine indicates that an experimental drug currently undergoing clinical trials for cancer treatment may enhance the effectiveness of first-line therapies for tuberculosis (TB) by facilitating a milder form of cell death in infected cells. This groundbreaking study, which was funded by the National Institutes of Health and published in the journal Nature Communications on March 27, points to the potential for developing more efficient and less damaging treatment options that could minimize lung damage among TB survivors. Moreover, these advances might help avert long-term lung complications, a condition increasingly recognized as post-TB lung disease that afflicts millions of former TB patients.
“Existing TB treatment protocols are not only lengthy and costly but also leave patients susceptible to relapse and lung damage. Our findings suggest that integrating a host-directed therapy could significantly address these challenges,” commented Sanjay Jain, M.D., a pediatric infectious diseases specialist and senior author of the study.
Despite being preventable and treatable, TB is once again a leading global cause of mortality, with estimates indicating 1.25 million deaths and 10.8 million new infections in 2023, as reported by the World Health Organization. A significant number of these cases involve strains that are resistant to conventional antibiotic treatments, complicating recovery efforts.
The causative agent of TB is the bacterium Mycobacterium tuberculosis. In its early stages, infected lung cells undergo apoptosis, a strictly regulated process leading to programmed cell death, which serves to restrain the spread of the bacteria. However, in later stages of the infection, uncontrolled necrosis—a more chaotic form of cell death—occurs, resulting in severe inflammation and damage to the surrounding lung tissue. Jain likens apoptosis to the controlled demolition of a building, while necrosis resembles the devastation caused by a bomb.
The TB bacterium manipulates the internal mechanisms of infected cells by promoting the production of Bcl-2 proteins, which are known for their anti-apoptotic properties. This interference with the natural apoptotic process provides several advantages to M. tuberculosis, as noted by Medha Singh, Ph.D., the study’s lead author. It results in necrotic conditions that shield the bacteria from immune system responses, thereby facilitating their proliferation.
While previous studies have explored the idea of inhibiting Bcl-2 as a potential TB treatment strategy, Singh points out that this host-directed approach, focusing on the infected cells rather than the bacteria itself, had not been tested in conjunction with a conventional TB treatment regime until now.
In the current research, the team treated mice infected with M. tuberculosis using a standard combination of antibiotics—rifampin, isoniazid, and pyrazinamide (RHZ)—while co-administering navitoclax, a Bcl-2 inhibitor that is already in clinical trials for cancer treatment.
Results revealed that mice receiving both RHZ and navitoclax exhibited a 40% reduction in necrotic lung lesions compared to those treated with RHZ alone. Furthermore, the risk of infection spreading to other organs, such as the spleen, was significantly lower over a four-week treatment period. Imaging techniques, including clinically applicable positron emission tomography (PET) for assessing apoptosis and lung fibrosis, showed that combining navitoclax with RHZ doubled the rate of pulmonary apoptosis and cut down lung scarring by 40% compared to conventional treatments, according to Laurence Carroll, Ph.D., an author of the study.
While navitoclax alone did not directly affect M. tuberculosis, its combination with RHZ proved 16 times more effective in reducing the bacterial load in the subjects. This data prompts speculation that navitoclax may not only be beneficial for TB patients but also for those suffering from other chronic bacterial infections, such as Staphylococcus aureus and non-TB mycobacteria, which are common in the United States.
Jain concludes that future clinical trials will be essential to validate these findings, particularly using innovative PET imaging methods developed at the Johns Hopkins Center for Infection and Inflammation Imaging Research. Successful trials could one day lead to the incorporation of navitoclax or similar agents into the standard antibiotic regimen, thereby shortening the conventional six-month treatment duration, decreasing the risk of lung damage, and enhancing patient outcomes in cases of drug-resistant TB.
Other contributors to this research from Johns Hopkins include Mona Sarhan, Nerketa Damiba, Alok Singh, Andres Villabona-Rueda, Oscar Nino-Meza, Xueyi Chen, Yuderleys Masias-Leon, Carlos Ruiz-Gonzalez, Alvaro Ordonez, and Franco D’Alessio.
This study was made possible through funding from various grants provided by the National Institutes of Health.
No conflicts of interest have been reported by the authors in accordance with the policies of the Johns Hopkins University School of Medicine.
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