NIHR Southampton Respiratory
Biomedical Research Unit
The Southampton Respiratory Biomedical Research Unit is funded by the National Institute for Health Research (NIHR)
and is a partnership between University Hospital Southampton Foundation Trust and the University of Southampton.
Developing novel approaches to control
multi-drug resistant tuberculosis through
interdisciplinary research
Paul Elkington
Faculty of Medicine
Southampton Centre for
Biomedical Research
NIHR Southampton Respiratory
Biomedical Research Unit
TB drug resistance is progressing
Overall TB incidence
Multi-drug resistant TB: 1990’s
Extensively-drug resistant TB: 2005
Totally-drug resistant TB: 2012
NIHR Southampton Respiratory
Biomedical Research Unit
Better understanding of the TB life cycle is required
Science Trans Med 2011 71: ps6 J Infection 2013 66: 299 Lancet Inf Dis 2015 15: 1357
Science 2010 328: 852 Nature 2013 502: S2 Nat Immunol 2014 16: 57 Cell 2014: 159: 1497
Established dogma: Southampton paradigm:
NIHR Southampton Respiratory
Biomedical Research Unit
Lung destruction is key to the success of TB
• Drives transmission
• Causes morbidity and mortality
• Suggests matrix metalloproteinase enzymes are key mediators
6/6 sputum samples positive for bacilli
NIHR Southampton Respiratory
Biomedical Research Unit
Matrix metalloproteinase-1 is the dominant
collagenase causing lung destruction in TB
Elkington et al J Clin Invest 2011 121: 1827
Walker et al AJRCCM 2012 185: 989
NIHR Southampton Respiratory
Biomedical Research Unit
Developing a 3-D model to address cell-matrix regulation of immune response to TB
Primary human cells
Cells + Alginate + / - Human Collagen
+ / - Tuberculosis
Syringe pump 10ml/h
1cm
7kV
500µm
Gelling bath with 100mM CaCl2
Alginate-Collagen microbeads
Multiparameter readouts:
Mtb growth Cell survival and proliferation Cell energy balance Cellular aggregation MMP secretion Cytokine secretion ECM breakdown
Suwan Jayasinghe
Workman et al Advanced Functional Materials 2014 24:2648
NIHR Southampton Respiratory
Biomedical Research Unit
Seddon et al J Infect Dis 2013 208: 1571
Sathyamoorthy et al PLOS One 2015 e0117605
Matrix breakdown releases collagen fragments that are novel TB diagnostic markers
NIHR Southampton Respiratory
Biomedical Research Unit
Novel TB biomarkers
Population screening to identify infectious patients
3-D cell culture
Novel antibiotics
Near patient diagnostic
Interrupt transmission cycle ↓ adult TB ↓↓ paediatric TB
Improved therapeutic approaches
Clinical trials to improve outcome and reduce infectivity
Mathematical modelling
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Bioinformatics
Southampton TB research
NIHR Southampton Respiratory
Biomedical Research Unit
University of Southampton
Liku Tezera
Magdalena Bielecka
Salah Mansour
Patience Brace
Andy Chancellor
Diana Garay
Elena Konstantinopoulou
Chidinma Odoh
Collaborators
Christopher Woelk
Spiro Garbis
Christine Currie
Xunli Zhang
Robert Zmijan
Imperial College
Jon Friedland
Naomi Walker
Dept of Engineering, UCL
Suwan Jayasinghe
Vicki Workman
Public Health England, Porton Down
Ann Williams
Simon Clark
University of Cape Town
Rob Wilkinson
Graeme Meintjes
K-RITH, Durban
Victoria Kasprowicz
All the patients who
have taken part
Acknowledgements
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