Abstract
Background
Pulmonary non-tuberculous mycobacterial (NTM)infections are increasing rapidly in the UK. The commonest pulmonary NTM infection outside the setting of cystic fibrosis lung disease is with the my cobacterium avium complex (MAC), consisting of M. avium and M. intracellulare. Patients with pulmonary MAC infection present with cavitatory lung disease ornodular bronchiectasis. Prolonged treatment is required, frequentlynot tolerated, and often associated with progressive lung destruction. A large body of evidence suggests the tissue damagethat occurs in tuberculous lung disease is driven by host derivedmatrix metalloproteinases (MMPs), in particular MMP-1 and 9.The mechanisms of tissue damage in NTM infection are not understood. We hypothesised that NTM drives MMP secretio nand that this drives cavitation and bronchiectasis.
Methods Monocytes isolated from healthy human volunteer blood by density centrifugation were stimulated with M. avium clinical isolates for 24 hours. Human monocyte-derived macrophages(MDMs) were generated from monocytes through 5–7day incubation with GM-CSF before stimulation with four different clinical isolates of M. avium for up to 72 hours. mRNA expression was investigated using qRT-PCR. Protein in cell supernatants was quantified using ELISA and Luminex array techniques.
Results
Stimulation with M. avium does not increase MMP-9secretion in monocytes or macrophages. M. avium significantly increases gene expression of MMP-1 and induces MMP-1 secretionby MDMs (Figure 1). Additionally, M. avium drives inductionof MMP-7, an elastolytic enzyme (Figure 1), and reduces the secretion of TIMP-1; the major in vivo inhibitor of MMP-1.Conclusions Interestingly, unlike Mycobacterium tuberculosis orother chronic pulmonary pathogens such as Pseudomonas orHaemophilus influenzae, M. avium does not drive secretion of MMP-9 by infected mononuclear cells from healthy donors.Instead it drives functionally unopposed MMP-1, which was previously thought to be an M. tuberculosis-specific response. Datasuggest MMP-1 and 7 may drive the destructive pulmonary pathophysiology that characterises M. avium infection. This willbe further investigated with patient sputum samples and inflammatory cells.
Pulmonary non-tuberculous mycobacterial (NTM)infections are increasing rapidly in the UK. The commonest pulmonary NTM infection outside the setting of cystic fibrosis lung disease is with the my cobacterium avium complex (MAC), consisting of M. avium and M. intracellulare. Patients with pulmonary MAC infection present with cavitatory lung disease ornodular bronchiectasis. Prolonged treatment is required, frequentlynot tolerated, and often associated with progressive lung destruction. A large body of evidence suggests the tissue damagethat occurs in tuberculous lung disease is driven by host derivedmatrix metalloproteinases (MMPs), in particular MMP-1 and 9.The mechanisms of tissue damage in NTM infection are not understood. We hypothesised that NTM drives MMP secretio nand that this drives cavitation and bronchiectasis.
Methods Monocytes isolated from healthy human volunteer blood by density centrifugation were stimulated with M. avium clinical isolates for 24 hours. Human monocyte-derived macrophages(MDMs) were generated from monocytes through 5–7day incubation with GM-CSF before stimulation with four different clinical isolates of M. avium for up to 72 hours. mRNA expression was investigated using qRT-PCR. Protein in cell supernatants was quantified using ELISA and Luminex array techniques.
Results
Stimulation with M. avium does not increase MMP-9secretion in monocytes or macrophages. M. avium significantly increases gene expression of MMP-1 and induces MMP-1 secretionby MDMs (Figure 1). Additionally, M. avium drives inductionof MMP-7, an elastolytic enzyme (Figure 1), and reduces the secretion of TIMP-1; the major in vivo inhibitor of MMP-1.Conclusions Interestingly, unlike Mycobacterium tuberculosis orother chronic pulmonary pathogens such as Pseudomonas orHaemophilus influenzae, M. avium does not drive secretion of MMP-9 by infected mononuclear cells from healthy donors.Instead it drives functionally unopposed MMP-1, which was previously thought to be an M. tuberculosis-specific response. Datasuggest MMP-1 and 7 may drive the destructive pulmonary pathophysiology that characterises M. avium infection. This willbe further investigated with patient sputum samples and inflammatory cells.
Original language | English |
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Article number | s 38 |
Pages (from-to) | 1-1 |
Journal | Thorax |
Volume | 71 |
Issue number | Supplament 3 |
Early online date | 15 Nov 2016 |
DOIs | |
Publication status | Published - 01 Dec 2016 |
Event | British Thoracic Society, Winter Meeting - QEII Centre, Westminster, London, United Kingdom Duration: 07 Dec 2016 → 09 Dec 2016 |
Keywords
- Mycobacterium avium
- Lung
- MMPs
- Infectious Diseases
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Dive into the research topics of 'Clinical isolates of Mycobacterium avium drive collagenolytic and elastolytic activity in mononuclear cells'. Together they form a unique fingerprint.Student theses
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Investigation of the host-mediated proteolytic response to pulmonary Mycobacterium Avium Complex infection
McFetridge, S. (Author), O'Kane, C. (Supervisor), McMullan, R. (Supervisor) & Schroeder, G. (Supervisor), Jul 2020Student thesis: Doctoral Thesis › Doctor of Philosophy
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