Investigation of Mechanotransduction in Tuberculosis in Search of Therapeutic Targets

In modern biology, the significance of cell-matrix interactions in shaping cellular behaviour is increasingly recognised, with emphasis on biochemical composition, 3D organisation, and mechanical properties. While this mechanistic signalling has gained substantial attention in cancer and stem cell research, its role in infection biology has often been overlooked. In Tuberculosis (TB), mycobacteria and host cells inhabit complex mechanical microenvironments. Indeed, TB is characterised by extracellular matrix (ECM) remodelling, emphasising the need to comprehend the mechanical dynamics of the ECM to gain insights into infection outcomes. Despite its potential importance, the mechanisms by which mechanoregulation influences cellular pathways and shapes host-pathogen interactions remain largely unexplored. I hypothesise that in TB, both the host and pathogen's ability to sense and respond to mechanical cues within the matrix environment dictates the heterogeneous outcomes observed in TB infection. To address this hypothesis, my research aims to examine host-pathogen interactions within a biomimetic TB infection model featuring varied matrix stiffness. Additionally, I aim to dissect the mechanotransduction-initiated pathways in mycobacterial-infected monocytes. Finally, I will also evaluate the mechanical effect of ECM in patient-derived samples, utilising matrices obtained from TB-infected lungs and corroborating results through immunohistochemistry studies. By defining optimal matrix stiffness reflective of distinct aspects of lung lesions and identifying critical mechanotransduction networks with therapeutic potential, this research aims to elucidate novel avenues for TB treatment.