Janet Zambezi Poster 2025

Ms Janet Zambezi

MRC The Gambia at LSHTM, The Gambia

The effect of N-acetyl cysteine on oxidative pathways leading to lung damage in Tuberculosis

Poster Abstract

Introduction: A significant proportion of Tuberculosis (TB) patients develop post-TB lung disease (PTLD). Despite its impact, scientific knowledge about PTLD remains limited. Host immunity against Mycobacterium tuberculosis (Mtb) triggers intra-pulmonary inflammation and consequently oxidative stress, which likely plays a key role in the development of PTLD through tissue damage. Neutrophils, which mediate lung inflammation, undergo ROS-dependent necrosis, leading to enhanced mycobacterial growth, further exacerbating oxidative stress. Host-directed therapies (HDT) such as N-acetyl cysteine (NAC) have been proposed to improve TB outcomes. NAC increases intracellular glutathione (GSH), an antioxidant that reduces reactive oxygen species (ROS) thereby potentially reducing lung damage. While NAC has shown promise in improving lung function in TB, the underlying host immune mechanisms remain unclear. My research, integrated within an HDT clinical trial assessing the use of NAC for the prevention and treatment of PTLD, will explore these mechanisms, focusing on neutrophil function and heterogeneity.

Methods: 80 participants with drug-sensitive TB presenting with moderate to severe lung impairment will be randomised to receive standard TB treatment with or without NAC for 6 months. Participants will be followed up for a further 6 months to assess lung function by spirometry and TB outcomes. An Mtb-H37Rv:mCherry strain will be used in whole blood infection assays to evaluate neutrophil and T-cell effector functions in both groups at baseline and 8 follow-up time-points. Baseline whole blood GSH levels in the Gambian population will be established using healthy volunteers and monitored in TB patients from recruitment to 12 months. Disease severity-associated neutrophil markers will be analysed using a multiparameter cytokine assay.

Implications: The correlation between NAC adjunct therapy, oxidative stress, and lung function will support its use as an HDT, optimizing its role in PTLD prevention and management.