The effect of potential host-directed therapies on the control of mycobacterial infection

Abstract

Before the COVID-19 pandemic, tuberculosis (TB) remained the leading cause of death among bacterial infectious diseases, particularly in developing regions such as Southern Africa with high human immunodeficiency virus (HIV) co-infection rates.. The emergence of drug- resistant TB strains further exacerbates the global burden. Key challenges in TB treatment include prolonged therapy duration and extensive lung damage. Host-directed therapies (HDTs) have been proposed as adjuncts to standard TB regimens to mitigate inflammation, reduce lung injury, and potentially shorten treatment duration. Despite promising results in animal models, clinical trials for HDTs are still in the early stages. This study evaluated two candidate HDTs—aspirin (ASA) and ibuprofen (IBU)—for their potential synergy with anti- TB drugs. Using a THP-1 human macrophage in vitro model, ASA and IBU were tested alongside standard TB drugs. Additionally, a retrospective analysis of clinical samples from a prospective cohort study assessed the effect of adjunctive IBU in TB treatment. The mycobacterial growth inhibition assay (MGIA) was used to measure the ability of peripheral blood mononuclear cells (PBMCs) from IBU-treated individuals to control Mycobacterium tuberculosis (M.tb) infection. Results from an XDR-TB pilot study showed no significant improvement in bacterial clearance with IBU. Further investigation revealed no significant impact of ASA or IBU on mycobacterial control in THP-1 macrophages or MGIA. Additionally, different M.tb strains exhibited no differential responses to these treatments. These findings suggest ASA and IBU do not influence TB infection outcomes, highlighting the need for alternative therapeutic strategies.