title: Dissection of the host-pathogen interaction in human tuberculosis using a bioengineered 3-dimensional model.
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.
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Liku B
authors.initials: LB
authors.lastname: Tezera
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Magdalena K
authors.initials: MK
authors.lastname: Bielecka
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chancellor
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Michaela T
authors.initials: MT
authors.lastname: Reichmann
authors.affiliation: King Abdullah International Medical Research Center/King Saud bin Abdulaziz University for Health Sciences, Department of Infectious Diseases, MNGHA, Riyadh, Saudi Arabia.
authors.forename: Basim Al
authors.initials: BA
authors.lastname: Shammari
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Patience
authors.initials: P
authors.lastname: Brace
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Batty
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Annie
authors.initials: A
authors.lastname: Tocheva
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Jogai
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Ben G
authors.initials: BG
authors.lastname: Marshall
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Marc
authors.initials: M
authors.lastname: Tebruegge
authors.affiliation: BioPhysics Group, UCL Institute of Biomedical Engineering, UCL Centre for Stem Cells and Regenerative Medicine and UCL Department of Mechanical Engineering, University College London, London, United Kingdom.
authors.forename: Suwan N
authors.initials: SN
authors.lastname: Jayasinghe
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.|Institute for Life Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Salah
authors.initials: S
authors.lastname: Mansour
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.|Institute for Life Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Paul T
authors.identifier: 0000-0003-0390-0613
authors.initials: PT
authors.lastname: Elkington
mesh_terms: D000464:Alginates / Q000737:chemistry; D000942:Antigens, Bacterial / Q000494:pharmacology; D001426:Bacterial Proteins / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000378:metabolism; D018920:Coculture Techniques; D003094:Collagen / Q000737:chemistry; D015232:Dinoprostone / Q000494:pharmacology; D005109:Extracellular Matrix / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation; D020723:Glucuronic Acid / Q000737:chemistry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000378:metabolism; D006603:Hexuronic Acids / Q000737:chemistry; D054884:Host-Pathogen Interactions / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D008863:Microspheres; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology; D018874:Spheroids, Cellular / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D014774:Virulence
chemical_list: D000464:Alginates; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C111835:CCL2 protein, human; C117940:CFP-10 protein, Mycobacterium tuberculosis; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D006603:Hexuronic Acids; C508585:IL1B protein, human; D053583:Interleukin-1beta; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020723:Glucuronic Acid; D003094:Collagen; D015232:Dinoprostone
keywords: Mycobacterium tuberculosis; bioengineering; extracellular matrix; human; immunology; infectious disease; microbiology; modelling