For millennia, tuberculosis (TB) has been a formidable scourge on humanity, outlasting countless attempts to eradicate it. Now, scientists are enlisting live, three-dimensional human lung tissue grown in labs to finally uncover the secrets of this ancient killer.
To understand why this new research is so pivotal, one must first understand the unique relationship between the TB bacterium and the human lung.
Accounts for about 85% of the global TB disease burden 1 . It's not just an infection that happens to be in the lungs; it is a disease whose progression is intimately tied to the lung's unique cellular environment.
Recent scientific investigations highlight that the progression of TB involves a deleterious bi-directional interaction between infected immune cells and the lung's own structural cells 1 . The lung tissue itself appears to be an active participant in the disease.
When someone with active pulmonary TB coughs, they release tiny, infectious droplets into the air.
If inhaled by another person, the bacteria find their way to the alveoli—the delicate air sacs of the lungs.
Alveolar macrophages engulf the invaders, attempting to contain the infection.
In most cases, granulomas form creating latent infection. In 5-10% of cases, containment fails leading to active disease.
Approximate distribution of TB infection outcomes in immunocompetent individuals.
The limitations of traditional models prompted a paradigm shift in how scientists model TB, moving beyond the two-dimensional world of a petri dish.
A single layer of cells grown in a flat dish. Simple and inexpensive but lacks 3D tissue structure.
Live mice infected with TB bacteria. Allows study of a whole living immune system but often doesn't form human-like granulomas.
Miniaturized tissue constructs that recapitulate human lung architecture and can form early granuloma-like structures 4 .
| Model Type | Key Advantages | Key Limitations |
|---|---|---|
| 2D Cell Culture | Simple, inexpensive, good for initial drug screening | Lacks 3D tissue structure and cell-cell interactions |
| Mouse Models | Allows study of a whole living immune system | Often doesn't form human-like granulomas; immune response differs from humans |
| 3D Lung Tissue Model | Recapitulates human lung architecture and cell interactions 4 | Lacks a full, systemic immune system; complex to create and maintain |
| Bovine Pulmosphere Model | Accurately mimics lung multicellularity, hypoxia, and stress gradients 8 | Species-specific, findings may not be directly translatable to human TB |
Human lung fibroblasts embedded in collagen matrix create the foundational layer.
Bronchial epithelial cells are seeded on top of the fibroblast-collagen layer.
Tissue exposed to air triggers differentiation and mucus production.
Macrophages infected with fluorescent TB bacteria are added to the model.
A recent study published in Communications Biology in 2025 developed a sophisticated 3D "bovine pulmosphere" model from primary bovine lung cells 8 .
This model demonstrated that pulmospheres develop hypoxic cores and gradients of nutrients, mirroring the stressful conditions found within real TB granulomas.
To illustrate the power of this approach, let's examine a seminal experiment that utilized a 3D human lung tissue model to study TB 4 .
The experimental procedure was a meticulous process of assembling a living tissue:
| Reagent / Material | Function |
|---|---|
| Human Lung Fibroblasts | Provides structural framework and extracellular matrix 4 |
| Human Bronchial Epithelial Cells | Forms protective, mucus-producing airway lining 4 |
| Type I Bovine Collagen | Scaffold that holds cell types in 3D structure 4 |
| Transwell Inserts | Platform enabling air-liquid interface 4 |
| Primary Human Macrophages | Immune cells that form the core of granulomas 4 |
| Fluorescently Tagged M. tuberculosis | Allows visual tracking of bacteria within tissue 4 8 |
The infected macrophages, when introduced to the 3D lung model, did not remain static.
They actively migrated into the deep tissue layers and began to aggregate with other cells, forming organized structures that closely resembled the early stages of human TB granulomas 4 .
For the first time, scientists could visually observe and quantitatively analyze the initial steps of granuloma formation in a human-relevant system. The experiment demonstrated that the lung tissue microenvironment provides essential signals that guide immune cell behavior and granuloma organization.
The implications of these lung tissue models are profound and are already opening new frontiers in the fight against TB.
Research revealed that aberrantly activated macrophages interacting with inflammation-injured lung epithelial cells create a TB-promoting environment 1 .
The cellular composition of the lung itself, not just its oxygenation, is a critical determinant of TB progression.
3D models provide a human-relevant platform for high-throughput drug screening.
The bovine pulmosphere model identified a six-gene/protein signature as an early host response marker to infection 8 . Such biomarkers can help rapidly evaluate new drug candidates.
In the future, it may be possible to create lung models using a patient's own cells.
This would allow doctors to test which TB drug regimens work best for that individual's specific infection, particularly promising for tackling drug-resistant TB.
| Research Area | Question Being Explored | Contribution of 3D Models |
|---|---|---|
| Disease Pathogenesis | Why does TB primarily progress in the lungs? | Identified deleterious macrophage-lung cell interactions and showed lung-specific vulnerability is cell-driven 1 |
| Drug Discovery | Can we find new drugs that work in a human-relevant environment? | Provides platform for screening compounds against TB in granuloma-like structures 8 |
| Host-Directed Therapies | Can we treat TB by modulating the human immune response? | Enabled discovery of early host-response biomarkers, revealing new therapeutic targets 8 |
| Diagnostic Development | Can we detect TB earlier based on the host's response? | Helps identify specific protein or gene signatures released by infected lung tissue |
The battle against tuberculosis is being waged on a new frontier—one that is measured in millimeters and grown in incubators. These tiny, lab-grown lungs are more than just scientific curiosities; they are powerful tools providing an unprecedented window into a disease that has plagued humanity for centuries.