From 2D to 3D: decoding tuberculosis pathobiology and drug development with ex vivo disease models

Abstract

Tuberculosis (TB) remains a global health challenge, requiring advanced models to understand its complex pathobiology and develop effective treatments. Despite extensive research, TB evades full understanding and control due to its complex interaction with the human immune system and latent state. Ex vivo models are essential for capturing these complexities and advancing TB research. Historically, TB research relied on two-dimensional (2D) cell cultures and animal models, which fell short of replicating the intricate lung environment. The advent of three-dimensional (3D) ex vivo models marks a significant leap forward, offering more physiologically relevant systems. These models, including spheroid cultures, organoid cultures, and lab-on-a-chip technologies, accurately represent human lung tissue and its interaction with Mycobacterium tuberculosis. 3D ex vivo models replicate the cellular diversity, architecture, and microenvironment of lung tissue, enabling detailed studies of TB pathogenesis, immune response, and granuloma formation. They also offer superior platforms for drug screening for efficacy and toxicity. Integrating microfluidics, advanced imaging techniques, and omics-based analytical platforms enhances these models' ability to simulate dynamic infection and treatment processes. This review highlights the development and transformative impact of ex vivo models on TB research, promising accelerated discovery of new therapeutic strategies.