Dissection of the host-pathogen interaction in human tuberculosis using a bioengineered 3-dimensional model
- University of Southampton, United Kingdom
- King Abdullah International Medical Research Center, Saudi Arabia
- University College London, United Kingdom
Abstract
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.
Article and author information
Author details
Funding
Medical Research Council (MR/N006631/1)
- Paul T Elkington
National Institute of Allergy and Infectious Diseases (R33AI102239)
- Suwan N Jayasinghe
- Paul T Elkington
National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/L001039/1)
- Liku B Tezera
- Paul T Elkington
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: For analysis of blood from healthy donors and healthy TB exposed individuals, this work was approved by the National Research Ethics Service committee South Central - Southampton A, study title 'An investigation into the immune response to tuberculosis infection and development of novel diagnostic markers', reference 13/SC/0043. All donors gave written informed consent. For histological analysis, samples used in this study were sourced from the Southampton Research Biorepository, University Hospital Southampton NHS Foundation Trust and University of Southampton, Mailpoint 218, Tremona Road, Southampton, SO16 6YD. Lung biopsy tissue was taken as part of routine clinical care and tissue blocks excess to diagnostic testing were analyzed in this study. The project was approved by the Institutional Review Board (Reference 12/NW/0794 SRB04_14). The ethics committee approved the analysis of this tissue without individual informed consent since it was surplus archived tissue taken as part of routine care.
Copyright
© 2017, Tezera et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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