Tuberculosis (TB) remains a global pandemic and drug resistance is rising. Multicellular granuloma
formation is the pathological hallmark of Mycobacterium tuberculosis (Mtb) infection. The membranetype
1 MMP (MT1-MMP or MMP-14) is a collagenase that is key in leukocyte migration and collagen
destruction. In patients with TB, induced sputum MT1-MMP mRNA levels were increased 5.1-fold
compared to matched controls and correlated positively with extent of lung infiltration on chest
radiographs (r=0.483; p<0.05). Mtb infection of primary human monocytes increased MT1-MMP
surface expression 31.7-fold and gene expression 24.5-fold. Mtb-infected monocytes degraded
collagen matrix in an MT1-MMP-dependent manner, and MT1-MMP neutralisation decreased collagen
degradation by 73%. In human TB granulomas, MT1-MMP immunoreactivity was observed in
macrophages throughout the granuloma. Monocyte-monocyte networks caused a 17.5-fold increase in
MT1-MMP surface expression dependent on p38 MAP kinase and GPCR-dependent signalling.
Monocytes migrating towards agarose beads impregnated with conditioned media from Mtb-infected
monocytes expressed MT1-MMP. Neutralization of MT1-MMP activity decreased this Mtb networkdependent
monocyte migration by 44%. Taken together, we demonstrate that MT1-MMP is central to
two key elements of TB pathogenesis, causing collagen degradation and regulating monocyte migration.