Clinical isolates of Mycobacterium avium drive collagenolytic and elastolytic activity in mononuclear cells

Research output: Contribution to journalMeeting abstractpeer-review

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.
Original languageEnglish
Article numbers 38
Pages (from-to)1-1
JournalThorax
Volume71
Issue numberSupplament 3
Early online date15 Nov 2016
DOIs
Publication statusPublished - 01 Dec 2016
EventBritish Thoracic Society, Winter Meeting - QEII Centre, Westminster, London, United Kingdom
Duration: 07 Dec 201609 Dec 2016

Keywords

  • Mycobacterium avium
  • Lung
  • MMPs
  • Infectious Diseases

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