Background: Corticosteroids (CTC) are ubiquitous in the field of respiratory medicine due to their potent anti-inflammatory and immune-modulating properties. The emergence of extreme multidrug resistant Mycobacterium Tuberculosis (Mtb) drives the need for improved host-directed therapies (HDT). CTC, such as dexamethasone, are the only approved adjunctive treatment for Mtb with neurological involvement. Despite the clinically proven effect of CTC, the exact mechanism of action is poorly understood.

Aim: To investigate the potential of dexamethasone as a HDT against Mtb.

Methods: Human Alveolar Macrophages (AM) were purified from bronchoalveolar lavage. Monocyte derived macrophages (MDM) were isolated and differentiated from blood of healthy individuals. Human macrophages were treated with dexamethasone and subsequently infected with Mtb. Macrophages were then assessed for cytokine secretion, metabolic gene expression, metabolic flux, and bacillary killing at multiple timepoints.

Results: In both AM and MDM, dexamethasone significantly reduced glycolysis and both pro and anti-inflammatory cytokines. Despite this, a reduction in the colony forming units (CFU) was observed. Furthermore, co-treating macrophages with an autophagy inhibitor (bafilomycin) prevents this decrease in CFU suggesting that dexamethasone likely enhances autophagy in human macrophages infected with Mtb. Moreover, dexamethasone has no direct bactericidal effect.

Conclusion: This study demonstrates the potential of dexamethasone as a HDT against Mtb highlighting the need for more studies and clinical trials to fully evaluate the benefits of CTC.