DECIPHERING THE BIOCHEMICAL AND BIOPHYSICAL MECHANISMS OF ACTION BY WHICH MT1-MMP, AS A CENTRAL PROTEASE, EXACERBATES BACTERIAL AND VIRAL INFECTION

Adi Buchshtab 1 Inna Solomonov 1 Michal Mandelboim 2,3 Roi Avraham 1 Irit Sagi 1
1Department of Biological Regulation, Weizmann institute, Rehovot, Israel
2National Center for Influenza and Respiratory Viruses in the Central Virology Laboratory, Sheba Medical Center in Tel-Hashomer, Ramat-Gan, Israel
3Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Matrix metalloproteinases (MMPs) have shown to play a crucial role in extracellular matrix remodeling in various pathophysiological tissue states. While the role of MMPs in cancer, arthritis, and neurodegenerative diseases has been explored extensively (1,2), the participation of MMPs as central proteases in infectious disease progression is relatively unknown. A recent study from our lab showed significant elevation in the expression of a tissue collagenase, membrane type 1 matrix metalloproteinase (MT1-MMP/MMP14), by macrophages during influenza infection (3). Inhibition of MT1-MMP by highly selective inhibitor suggested a novel host-oriented antipathogenic mechanism. Specifically, our results strongly suggest that MT1-MMP contributes to the progression of pathogen infection mechanisms by shedding cell surface ligands. Here, we investigate the molecular mechanisms by which MT1-MMP effects the course of infection. To achieve this, we established two in vitro infection models: infection of macrophages with salmonella and infection of lung epithelial cells with influenza. We used anti-MT1-MMP inhibitory antibody in order to specifically inhibit MT1-MMP proteolytic activity. Our results show a reduction in bacterial and viral entry after MT1-MMP inhibition. Overall, our results suggest that MT1-MMP proteolytic activity regulates host-pathogen interactions during early stages of both bacterial and viral infections.

  1. Bonnans, C., J. Chou, and Z. Werb, Remodelling the extracellular matrix in development and disease. Nature reviews Molecular cell biology, 2014. 15(12): p. 786-801.
  2. Lu, P., et al., Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harbor perspectives in biology, 2011. 3(12): p. a005058.
  3. Talmi-Frank, D., et al., Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality. Cell host & microbe, 2016. 20(4): p. 458-470.








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