Dissection of the host-pathogen interaction in human tuberculosis using a bioengineered 3-dimensional model.
Liku B TezeraMagdalena K BieleckaAndrew ChancellorMichaela T ReichmannBasim Al ShammariPatience BraceAlex BattyAnnie TochevaSanjay JogaiBen G MarshallMarc TebrueggeSuwan N JayasingheSalah MansourPaul T ElkingtonPublished in: eLife (2017)
Cell biology differs between traditional cell culture and 3-dimensional (3-D) systems, and is modulated by the extracellular matrix. Experimentation in 3-D presents challenges, especially with virulent pathogens. Mycobacterium tuberculosis (Mtb) kills more humans than any other infection and is characterised by a spatially organised immune response and extracellular matrix remodelling. We developed a 3-D system incorporating virulent mycobacteria, primary human blood mononuclear cells and collagen-alginate matrix to dissect the host-pathogen interaction. Infection in 3-D led to greater cellular survival and permitted longitudinal analysis over 21 days. Key features of human tuberculosis develop, and extracellular matrix integrity favours the host over the pathogen. We optimised multiparameter readouts to study emerging therapeutic interventions: cytokine supplementation, host-directed therapy and immunoaugmentation. Each intervention modulates the host-pathogen interaction, but has both beneficial and harmful effects. This methodology has wide applicability to investigate infectious, inflammatory and neoplastic diseases and develop novel drug regimes and vaccination approaches.
Keyphrases
- extracellular matrix
- mycobacterium tuberculosis
- endothelial cells
- immune response
- pulmonary tuberculosis
- candida albicans
- randomized controlled trial
- pluripotent stem cells
- induced pluripotent stem cells
- induced apoptosis
- physical activity
- emergency department
- single cell
- cell therapy
- antimicrobial resistance
- hepatitis c virus
- cell proliferation
- gram negative
- cross sectional
- inflammatory response
- human immunodeficiency virus