Breakthrough Findings from A*STAR ID Labs on Persistent Lung Vulnerabilities

The Agency for Science, Technology and Research (A*STAR) Infectious Diseases Labs (A*STAR ID Labs) has published a groundbreaking study in Nature Communications revealing why patients face ongoing lung health challenges even after successful tuberculosis (TB) treatment. Titled "Primary tuberculous mycobacterial granulomas provide a niche for superinfecting Mycobacterium abscessus," the research demonstrates that TB-induced granulomas—structured clusters of immune cells—persist in the lungs and create protective environments, or "safe houses," for opportunistic pathogens.

Led by Principal Investigator Dr. Stefan Oehlers and Senior Principal Investigator Dr. Amit Singhal, both affiliated with A*STAR ID Labs and the Lee Kong Chian School of Medicine at Nanyang Technological University (NTU) Singapore, the study used advanced zebrafish models to mimic human TB pathology. This collaboration between A*STAR's research prowess and NTU's academic expertise underscores Singapore's integrated approach to biomedical innovation.

In Singapore, where TB remains endemic despite control efforts, these insights are particularly timely. With 1,019 new active TB cases reported in 2025—a decline from 1,156 in 2024—the nation's incidence rate dropped to 24.2 per 100,000 population. Yet, post-TB lung disease (PTLD) poses a hidden burden, especially as nontuberculous mycobacteria (NTM) like M. abscessus infections rise, often linked to prior TB.

Understanding Tuberculosis and Its Lasting Lung Impact in Singapore

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), primarily affects the lungs and spreads via airborne droplets from prolonged close contact with infected individuals. Singapore's National Tuberculosis Programme (NTBP), managed by the Communicable Diseases Agency (CDA) under the Ministry of Health (MOH), has successfully reduced cases through screening, directly observed treatment (DOT), and contact tracing. Despite this, older adults and males remain at higher risk, with 11 TB-related deaths in 2025.

Post-TB lung disease refers to chronic respiratory impairments persisting after microbiological cure. Globally, an estimated 155 million TB survivors live with PTLD, facing heightened risks of chronic obstructive pulmonary disease (COPD), bronchiectasis, pulmonary hypertension, and even a fourfold increase in lung cancer odds. In Singapore, where NTM pulmonary infections have doubled over two decades and now rival TB incidence, prior TB history is the leading predisposing factor for M. abscessus disease.

The Role of Granulomas: Immune Fortresses Turned Pathogen Havens

Granulomas form as the body's defense against Mtb: immune cells like macrophages aggregate around bacteria, creating walled-off structures filled with caseum—a cheese-like necrotic material produced via the ESX-1 virulence system. While containing primary infection, these granulomas often calcify and endure lifelong, even post-treatment.

The A*STAR study shows granulomas attract superinfecting pathogens. In zebrafish sequentially infected with primary M. marinum (TB proxy) followed by M. abscessus, secondary bacteria proliferated inside granulomas, evading macrophage killing and antibiotics like clarithromycin. Caseum served as a nutrient feast, enabling rapid growth in a lipid-rich niche separate from primary bacteria.

• Preferential colonization: Up to 40% granuloma occupancy by M. abscessus.
• Immune evasion: Reduced macrophage control inside granulomas.
• Antibiotic resistance: Treatment failed against niche-residing bacteria.

Similar patterns held for other opportunists: M. smegmatis, Aspergillus fumigatus, and Candida auris, highlighting granulomas as broad-risk niches.

Innovative Zebrafish Model Illuminates Human Pathology

Zebrafish offer optical transparency for live imaging and genetic tractability mimicking human granulomas. Adult fish modeled chronic infection; embryos enabled timelapse of pathogen ingress via vasculature into granulomas. Histology, RNA sequencing, and in vitro caseum assays confirmed mechanisms: ESX-1 drives caseum production, luring macrophages that ferry secondary pathogens inward.

Disrupting ESX-1 or pretreating primary infection reduced secondary colonization, suggesting early granuloma resolution therapies could prevent PTLD.Read the full study here.

Singapore's Rising NTM Threat and Post-TB Vulnerabilities

In Singapore, pulmonary NTM incidence approaches TB levels, with M. abscessus emerging dominant. One-third of NTM patients have prior TB, aligning with A*STAR's niche hypothesis. Treatment for M. abscessus demands years of multidrug therapy, straining patients and healthcare.

Dr. Oehlers notes: “TB treatment requires months of antibiotics; secondary infections demand years more. Early intervention on granulomas is key.” Dr. Caroline Choong from Tan Tock Seng Hospital adds: “Residual scarring leaves patients vulnerable—follow-up monitoring is essential.”

Global Burden of Post-TB Lung Disease

Worldwide, PTLD affects nearly half of survivors, contributing to 122 million disability-adjusted life years lost. Risks include airflow obstruction (65% higher odds), bronchiectasis, and lung cancer. In high-burden areas, PTLD mortality is 2-6 times higher in the first post-treatment year.

• COPD: TB sequela in 27.9% after 3 years.
• Bronchiectasis: Common structural damage.
• Lung cancer: 4x risk post-PTB.

Singapore's low-transmission setting amplifies the study: historical TB scars fuel modern NTM epidemics.Explore global PTLD risks.

Gaps in Current Post-TB Care and Singapore's Response

NTBP excels in detection and DOT but post-treatment surveillance lags. No routine PTLD screening exists, despite symptoms like breathlessness persisting in many. A*STAR advocates granuloma-resolving adjunct therapies and long-term monitoring.

Integrated efforts with NTU and hospitals could pioneer PTLD protocols, leveraging Singapore's biotech ecosystem.

Future Directions: From Research to Clinical Solutions

Oehlers' lab explores host-directed therapies targeting granuloma persistence. Potential: Anti-fibrotic drugs, immune modulators to clear niches. Singapore's RIE2030 invests S$800M in semiconductors and biomed, positioning A*STAR for PTLD innovations.

Clinically, imaging (CT scans) and spirometry post-TB could identify at-risk patients. Multidisciplinary care—pulmonologists, infectious disease specialists—essential.

Stakeholder Perspectives and Actionable Insights

MOH's CDA emphasizes community vigilance; patients report symptoms promptly. Researchers call for PTLD registries. For academics, opportunities abound in TB-host interactions.Singapore TB updates.

Photo by Kingsley Yang on Unsplash

Outlook: Safeguarding Lung Health Beyond TB Cure

A*STAR's discovery reframes TB as a lifelong commitment. By targeting granulomas, Singapore can lead in PTLD prevention, reducing NTM burdens and enhancing quality of life. Ongoing research promises therapies transforming post-TB recovery.