Journal
CELL HOST & MICROBE
Volume 20, Issue 4, Pages 458-470Publisher
CELL PRESS
DOI: 10.1016/j.chom.2016.09.005
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Funding
- Israeli Science Foundation [1226/13]
- Ambach fund
- Kimmelman center at the WIS
- European Research Council AdG [THZCALORIMETRY-DLV-695437]
- USA-Israel Binational Science Foundation [712506-01]
- European Research Council [309788]
- Israel Science foundation [703/15]
- BLUEPRINT FP7 consortium
- Minerva Stiftung research grant
- Helen and Martin Kimmel award
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Mounting an effective immune response, while also protecting tissue integrity, is critical for host survival. We used a combined genomic and proteomic approach to investigate the role of extracellular matrix (ECM) proteolysis in achieving this balance in the lung during influenza virus infection. We identified the membrane-tethered matrix metalloprotease MT1-MMP as a prominent host-ECM-remodeling collagenase in influenza infection. Selective inhibition of MT1-MMP protected the tissue from infection-related structural and compositional tissue damage. MT1-MMP inhibition did not significantly alter the immune response or cytokine expression. The available flu therapeutic Oseltamivir did not prevent lung ECM damage and was less effective than anti-MT1-MMP in influenza virus Streptococcus pneumoniae coinfection paradigms. Combination therapy of Oseltamivir with anti-MT1-MMP showed a strong synergistic effect and resulted in complete recovery of infected mice. This study highlights the importance of tissue resilience in surviving infection and the potential of such host-pathogen therapy combinations for respiratory infections.
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