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

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. [Display omitted] •MT1-MMP is a prominent lung tissue-remodeling collagenase during influenza infection•MT1-MMP-expressing myeloid cells cause collateral tissue damage following infection•MT1-MMP inhibition rescues tissue damage and mortality in influenza-infected mice•Oseltamivir and anti-MT1-MMP combination therapy results in complete recovery in mice Balancing tissue integrity with an effective immune response is critical for host survival. Talmi-Frank et al. identify MT1-MMP as a prominent extracellular matrix-remodeling collagenase active in influenza virus infection. Selective inhibition of MT1-MMP protected the tissue from structural and compositional damage and rescued mice from influenza-associated mortality.