Host-directed therapy for the treatment of tuberculosis: rewiring the host to recover control

Abstract

Tuberculosis (TB) remains a leading cause of global mortality, worsened by multidrug-resistant strains and dormant infections that evade conventional antibiotics. To address these challenges, this thesis explores Host-Directed Therapy (HDT), an approach that targets host cell pathways to enhance bacterial clearance and bypass bacterial resistance mechanisms.

The research establishes a robust framework for HDT discovery through a newly developed flow cytometry-based screening platform. Integrated with machine learning, this platform identifies host targets and chemical compounds involved in intracellular infection. Furthermore, the work demonstrates that structure-guided optimization can significantly refine HDT efficacy. It also reveals that diverse compounds, including repurposed clinical drugs, converge on shared mechanisms such as TFEB-mediated lysosomal activation and autophagy. Additionally, epigenetic modulation via HDAC inhibition emerged as a strategy to reprogram macrophage responses.

By validating these strategies across primary human cells and in vivo models, this thesis provides strong preclinical evidence that HDTs can complement existing regimens, combat drug resistance, and potentially shorten TB treatment duration.