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The Extracellular Matrix Regulates Granuloma Necrosis in Tuberculosis

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The Extracellular Matrix Regulates Granuloma Necrosis in Tuberculosis 1 2 The extracellular matrix regulates granuloma necrosis in tuberculosis 3 4 Basim Al shammari1 , Takayuki Shiomi2, Liku Tezera3, Magdalena K Bielecka3, Victoria Workman4, 5 Tarangini Sathyamoorthy1, Francesco Mauri5, Suwan N Jayasinghe4, Brian D Robertson6, Jeanine 6 D’Armiento2, # Jon S Friedland1, #, and Paul T Elkington1, 3,7* 7 1Infectious Diseases and Immunity, Department of Medicine, Imperial College London, UK. 8 2Department of Medicine, Columbia University, New York, USA. 3NIHR Respiratory Biomedical 9 Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University 10 of Southampton, UK. 4BioPhysics Group, UCL Institute of Biomedical Engineering, UCL Centre for 11 Stem Cells and Regenerative Medicine and UCL Department of Mechanical Engineering, University 12 College London, UK. 5Histopathology, Department of Medicine, Imperial College London, UK. 13 6MRC Centre for Molecular Bacteriology and Infection, Department of Medicine, Imperial College 14 London, UK. 7Institute for Life Sciences, University of Southampton, UK. 15 #These authors contributed equally 16 17 * Address for correspondence: 18 Dr Paul T Elkington 19 Clinical and Experimental Sciences 20 University of Southampton, Southampton SO16 1YD 21 Tel 00 44 23 8079 6671 22 E-mail: [email protected] 23 24 Running title: Tuberculosis and the matrix 25 1 26 Abstract 27 28 A central tenet of tuberculosis (TB) pathogenesis is that caseous necrosis leads to extracellular matrix 29 destruction and bacterial transmission. We reconsider the underlying mechanism of TB pathology and 30 demonstrate that collagen destruction may be a critical initial event, causing caseous necrosis as 31 opposed to resulting from it. In human TB granulomas, regions of extracellular matrix destruction 32 map to areas of caseous necrosis. In mice, transgenic expression of human matrix metalloproteinase- 33 1 causes caseous necrosis, the pathological hallmark of human TB. Collagen destruction is the 34 principal pathological difference to wild type mice, whereas the release of pro-inflammatory 35 cytokines does not differ, demonstrating that collagen breakdown may lead to cell death and 36 caseation. To investigate this hypothesis, we developed a 3-dimensional cell culture model of TB 37 granuloma formation utilising bioelectrospray technology. Collagen improved survival of 38 Mycobacterium tuberculosis-infected cells analyzed by LDH release, propidium iodide staining and 39 total viable cells. Taken together, these findings suggest that collagen destruction is an initial event in 40 TB immunopathology, leading to caseous necrosis and compromising the immune response, revealing 41 a previously unappreciated role for the extracellular matrix in regulating the host-pathogen 42 interaction. 43 44 Abstract word count: 184 45 46 Keywords: Tuberculosis, extracellular matrix, matrix metalloprotease, immunopathology 47 48 2 49 Introduction 50 51 The intensive biomedical research effort to develop new vaccination approaches and shorter treatment 52 regimens for tuberculosis (TB) have not yet resulted in significant changes to disease management 53 [1-3], suggesting that paradigms of pathogenesis may be incomplete. The pathophysiological 54 hallmark of TB is caseous necrosis, which is thought to result from Mycobacterium tuberculosis 55 (Mtb)-mediated macrophage cell death [4-6]. An excessive pro-inflammatory immune response may 56 exacerbate tissue destruction [7], and this concept of pathology informs novel vaccine and 57 immunomodulatory strategies [8, 9]. 58 59 In this model of TB pathology, caseous necrosis is proposed to cause tissue destruction, leading to 60 lung cavitation and transmission of infection [10, 11]. This long-established paradigm primarily 61 derives from classical experiments in the rabbit model of Mycobacterium bovis infection, where large 62 tubercules develop and then rupture into the airways [12]. However, dissection of the precise 63 sequence of events is limited by suitable animal models, since caseous necrosis is generally not 64 observed in immunocompetent mice [13]. Caseous necrosis is observed in TB granulomas of 65 humanised mice engrafted with fetal human liver and thymus tissue [14], while large regions of 66 necrosis may develop in mice that control Mtb proliferation poorly and develop a very high 67 mycobacterial load [15]. However, in human granulomas mycobacteria are very infrequent [16], and 68 therefore in human disease pathology is initially driven by a low mycobacterial load. 69 70 We have previously demonstrated that MMP-1 expressing mice develop collagen destruction within 71 granulomas when infected with the standard laboratory strain, Mtb H37Rv, and this collagen 72 destruction occurred in the absence of caseous necrosis [17]. However, the relationship between 73 matrix destruction and the cell death that forms caseous necrosis have not been systematically 74 examined, nor the consequences of matrix destruction on the interaction between host immune cells 75 and Mtb. We reconsider the sequence of events driving immunopathology in TB by studying human 3 76 lung biopsy tissue, mice expressing human MMPs and 3-dimensional cell culture systems, and 77 conclude that collagen destruction is an early event that increases host cell death. 78 4 79 80 Methods 81 Ethics statement: The project was approved by the Hammersmith and Queen Charlotte's & Chelsea 82 Research Ethics Committee, London (ref 07/H0707/120). Lung biopsy tissue was taken as part of 83 routine clinical care and processed for standard diagnostic testing. The residual tissue blocks not 84 required for diagnostic purposes were analyzed in this study and were released from the 85 Hammersmith Hospitals NHS Trust Human Biomaterials Resource centre. The ethics committee 86 approved the analysis of this tissue without individual informed consent since it was surplus archived 87 tissue taken as part of routine care. All animal experiments were approved by the Home Office of the 88 United Kingdom, which is responsible for approving laboratory animal care and experiments in the 89 UK, under project licence PPL 70-7160. All experiments were performed in accordance with the UK 90 Animal (Scientific Procedures) Act 1986 in the containment level 3 animal facility at Imperial 91 College London. For analysis of blood from healthy donors, this work was approved by the National 92 Research Ethics Service committee South Central - Southampton A (ref 13 SC 0043) and all donors 93 gave written informed consent. 94 Extracellular matrix staining in human lung biopsies: Lung biopsies from patients under 95 investigation for probable lung cancer who had pulmonary TB diagnosed as a result of the biopsy 96 appearances were studied. All patients had caseous necrosis, the pathognomonic appearance of 97 tuberculosis, and responded well to standard antibiotic treatment. Staining for Masson’s Trichrome, 98 Picrosirius red and Elastin Van Gieson was performed according to standard protocols. 99 Mouse M. tuberculosis infection protocol: All mice were bred on the C57BL6 background, which is 100 relatively resistant to infection with Mtb. Mice expressing human MMP-1 and -9 under control of the 101 scavenger receptor A promoter-enhancer and wild-type littermates were infected intranasally with 102 5,000 colony forming units M. tuberculosis that had recently been isolated from a patient with 103 pulmonary TB [18]. Preliminary studies demonstrated that this protocol reliably produced a 104 pulmonary deposition of approximately 500 CFU and caused giant cell formation, a characteristic 5 105 feature of human disease not caused by Mtb H37Rv in C57BL6 mice. In each experiment, there were 106 a minimum 5 mice per group and 3 separate experiments were performed. Mice were checked 107 regularly for signs of distress and weighed fortnightly. Mice were sacrificed by terminal overdose of 108 anaesthetic at 22 weeks and dissected as previously described [17]. For protein analysis and colony 109 counting, one lobe was homogenised in 1ml PBS. Colony counting was performed by plating on 110 Middlebrook 7H11 agar (BD Biosciences). Lung homogenate and BALF was sterilized through a 111 0.2μm filter (Millipore) [19]. 112 Luminex analysis: MMP and cytokine concentrations were analyzed on a Bioplex 200 platform 113 (Bio-Rad, Hemel Hempstead, U.K.) according to manufacturer’s protocol. MMP concentrations were 114 analysed by the MMP Fluorokine multianalyte profiling (R&D Systems, Abingdon, UK) and cytokine 115 concentrations were measured using the Cytokine mouse panel (Invitrogen, UK). 116 2-Dimensional In Vitro Granuloma (IVG) model: The model described by Altare’s group was 117 adapted [20]. Peripheral Blood Mononuclear Cells (PBMCs) were isolated from single donor buffy 118 coats from the National Blood Transfusion Service (Colindale, UK) or from healthy volunteers. 119 Leukocytes were isolated by density centrifugation over Ficoll Paque (Amersham Biosciences, UK). 120 Total PBMCs were plated in 24 well plate at 1x106 cells/well in 10% AB serum in RPMI 121 supplemented with 2mM glutamine and 10μg/ml ampicillin. PBMCs were infected with Mtb at a 122 multiplicity of infection (MOI) of 0.001. 123 DQ collagen degradation assay: PBMCs were resuspended in collagen mix solution: 8 parts sterile 124 collagen type I (Advanced BioMatrix, San Diego, CA) with DQ collagen (Invitrogen, Paisley, UK) in 125 1:7 ratio, and 1 part of sterile 10X RPMI, NaOH in HEPES and AB serum. pH was corrected to 7.0 126 using 7.5% NaHCO3.
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