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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 mycobacterium avium complex (MAC), consisting of M. avium and M. intracellulare. Patients with pulmonary MAC infection present with cavitatory lung disease or nodular bronchiectasis. Prolonged treatment is required, frequently not tolerated, and often associated with progressive lung destruction. A large body of evidence suggests the tissue damage that occurs in tuberculous lung disease is driven by host derived matrix 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 secretion and 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 5–7 day 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-9 secretion in monocytes or macrophages. M. avium significantly increases gene expression of MMP-1 and induces MMP-1 secretion by MDMs (Figure 1). Additionally, M. avium drives induction of 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 or other chronic pulmonary pathogens such as Pseudomonas or Haemophilus 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. Data suggest MMP-1 and −7 may drive the destructive pulmonary pathophysiology that characterises M. avium infection. This will be further investigated with patient sputum samples and inflammatory cells.
MMP-1 (left) and MMP-7 (right ) secretion from MDMs at 72 hours post stimulation with 4 different clinical isolates of M. avium