developing novel approaches to control multi-drug resistant … · 2016. 1. 11. · graeme meintjes...

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



TB drug resistance is progressing

Overall TB incidence

Multi-drug resistant TB: 1990’s

Extensively-drug resistant TB: 2005

Totally-drug resistant TB: 2012



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:



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



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



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



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



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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H s _ P 0 1 7 7 1 H s _ P 0 0 7 4 0H s _ P 2 9 9 6 5

H s _ P 5 1 6 0 8H s _ P 0 8 5 7 1

H s _ P 0 3 9 5 1 H s _ P 0 2 7 4 1H s _ Q 5 V TL 7 H s _ Q 5 T5 U 3

H s _ P 3 0 0 4 1 H s _ Q 8 I W G 1H s _ P 0 D J I 8

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p < 0 .0 1

Bioinformatics

Southampton TB research



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

developing novel approaches to control multi-drug resistant … · 2016. 1. 11. · graeme meintjes...

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