Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis

Area of Science:

• Immunology
• Pharmacology
• Infectious Diseases

Background:

• Mycobacterium tuberculosis infection triggers host cell anti-apoptotic responses, leading to necrosis, inflammation, and fibrosis.
• Current tuberculosis treatments can be lengthy and lung damage is a common sequela.

Purpose of the Study:

• To evaluate navitoclax, a Bcl-2 inhibitor, as a host-directed therapy to improve pulmonary tuberculosis treatment outcomes.
• To assess navitoclax's impact on bacterial clearance, tissue damage, and immune cell apoptosis in a mouse model of TB.

Main Methods:

• Mice with pulmonary tuberculosis were treated with standard therapy plus navitoclax at human-equivalent doses.
• Immunohistochemistry and flow cytometry were used to analyze immune cell populations and apoptosis.
• Positron emission tomography (PET) imaging with apoptosis and fibrosis biomarkers (18F-ICMT-11 and 18F-FAPI-74) was performed in live animals.

Main Results:

• Navitoclax treatment significantly improved bacterial clearance and reduced pulmonary necrosis and fibrosis.
• The drug induced apoptosis in immune cells, including CD68+ and CD11b+ populations.
• PET imaging confirmed increased apoptosis and reduced fibrosis in lung tissues, corroborated by postmortem analysis.

Conclusions:

• Navitoclax, as a host-directed therapy, shows significant promise in improving pulmonary tuberculosis treatment.
• Proapoptotic drugs like navitoclax can reduce lung damage and fibrosis, potentially mitigating long-term complications of TB.
• This approach may offer protection against the development of post-tuberculosis lung disease.