Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality

Dalit Talmi-Frank, Zeev Altboum, Inna Solomonov, Yael Udi, Diego Adhemar Jaitin, Mordehay Klepfish, Eyal David, Alina Zhuravlev, Hadas Keren-Shaul, Deborah R. Winter, Irit Gat-Viks, Michal Mandelboim, Tamar Ziv, Ido Amit*, Irit Sagi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)458-470
Number of pages13
JournalCell Host and Microbe
Volume20
Issue number4
DOIs
StatePublished - Oct 12 2016

Keywords

  • ECM remodeling
  • Influenza virus
  • MT1-MMP
  • host-pathogen gene regulation
  • immune genomics
  • matrix metalloproteinase inhibitors
  • viral-bacterial coinfection

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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