A global health challenge

Tuberculosis (TB) remains a formidable global health challenge as the leading infectious disease resulting in death. The infection causes potential long-lasting complications even after cure. Declared a global health emergency by the World Health Organization (WHO) in 1993, TB continues to have a worldwide impact—with one in four individuals infected with TB.

In 2023, there were approximately 10.8 million new cases and 1.25 million deaths globally. The rise of drug-resistant strains, specifically multidrug-resistant (MDR) and extensively drug‑resistant (XDR) TB, complicates the situation, limiting treatment options and threatening to escalate this epidemic further. Despite being a high-income country, Singapore is a middle-TB burden setting, a potent indicator of TB’s persistent grip.

Beyond lung damage, the disease may also result in cardiovascular complications. Survivors of TB are at increased risk of conditions such as TB pericarditis and acute coronary syndrome. Furthermore, long-term sequelae in the form of post-TB lung disease may be drivers of pulmonary hypertension, which may result in right heart failure. In literature, up to 47% of pulmonary TB survivors may be afflicted with pulmonary hypertension. The association between TB and cardiovascular disease highlights the need for further research into the long-term health consequences of TB and treatment options to improve patient quality of life.

Clinical studies

Associate Professor Catherine Ong, Assistant Dean (Research) at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) and Head of the NUHS Clinician-Scientist Academy, has clinical and research interest in mitigating TB immunopathology. Her research team comprises both clinicians and scientists with a specific focus on translational medicine that bridges laboratory insights with clinical application and utilises cellular and animal TB models in multinational clinical trials.

At the forefront of pioneering research into complex immune interactions between Mycobacterium tuberculosis and host factors driving immunopathology, the lab has conducted cross-sectional studies to explore immune dysregulation in patients with poorly-controlled diabetes who contract pulmonary TB—an area of critical importance given the global prevalence of both conditions. We found an upregulation of matrix metalloproteinases (MMPs), which drive inflammation in patients with pulmonary TB, and hyper-inflammatory immune dysregulation in pulmonary TB patients with poorly controlled diabetes, such as defective phagocytosis and hyper-responsive neutrophil inflammation.

This work is driven by PhD student Dr Thong Pei Min, now a Research Fellow at the National Centre for Infectious Diseases, and funded by the National Medical Research Council. Dr Thong won the Best Poster prize at the leading international Infectious Disease Congress—European Society of Clinical Microbiology and Infectious Diseases (ESCMID)—and was also awarded the National Centre for Infectious Disease Short Term Fellowship. This research sheds light on how metabolic disorders might alter immune responses, potentially guiding new treatment strategies. Patients with pulmonary TB who had poorly controlled diabetes also expressed higher angiogenic factors. Further investigation into this is being driven by Research Associate Mr Wong Yi Hao who has successfully developed a diabetic murine model of pulmonary TB and is currently working towards his PhD.

On the therapeutic front, our lab has conducted a randomised-controlled Phase 2 clinical trial, which has demonstrated the efficacy of host-directed therapies, such as doxycycline (an MMP inhibitor), in reducing the inflammatory transcriptome and immune-phenotype seen in pulmonary TB, with corresponding reduction of lung cavity volume. Through this study, we investigated host transcriptomics using bulk RNA sequencing and utilised bioinformatics to identify mechanistic immune signatures seen in TB.