Agent-Based Modeling of Cell Culture Granuloma Models: The Role of Structure, Dimension, Collagen, and Matrix Metalloproteinases

Tuberculosis (TB) remains a global public health crisis, causing over 10 million new infections and 1.3 million deaths in 2022 alone. TB is caused by Mycobacterium tuberculosis (Mtb), which initiates heterogeneous pathology in the lungs, including granulomas and cavities. Granulomas are organized structures of immune cells, traditionally thought to contain bacteria. Cavities are pathological spaces caused by the destruction of extracellular matrix (ECM), which can worsen disease outcomes and cause long-lasting pulmonary impairment. In vitro methods are commonly used to study host-pathogen interactions in Mtb infection, and recent developments have led to models that represent the TB granuloma environment more closely than traditional cell culture. These advances include the development of 3D models and the inclusion of physiological ECM components like collagen. Increasing complexity has been accomplished in a piece-wise manner – minimally necessary components are included to minimize cost while maintaining throughput and tractability. This creates a need for tools to analyze these systems and, more importantly, integrate the independent data created. We developed an agent-based model to characterize multiple in vitro models of TB and apply it to 1) separate the contributions of dimension and structure to bacterial control in granuloma-like spheroids and 2) explore how the interactions of collagen and matrix metalloproteinases (MMP) contribute to clinically relevant outputs such as bacterial load and ECM destruction. The model provides insights into the role of granuloma structure and the conflicting results of MMP inhibition, generating new hypotheses to be tested in tandem with in vitro models.