Dysregulated Proteolysis of Extracellular Matrix Proteins Regulates Influenza and Pneumonia Co-infection Associated Mortality

The balance between tissue integrity and efficient immune response is critical for host survival. Here we investigate the role of extra cellular matrix (ECM)-remodeling events in the lung during influenza infection. Using an unbiased genomic and proteomic approach we follow the dynamics of gene and ECM responses in an influenza-infected mouse model, integrated with whole tissue as well as ECM imaging and functional assays. Our study identifies membrane type 1 matrix metalloproteinase (MT1-MMP) as a major host-regulated ECM remodeling collagenase in influenza infection. We show that inhibition of MT1-MMP-driven proteolytic activity protected tissue structural and compositional features. We demonstrate that available influenza treatment (Oseltamivir) is ineffective in preventing the lung ECM damage and is therefore less effective than anti-MT1-MMP treatment in influenza and Streptococcus pneumoniae co-infections. Importantly, the combination between the two treatments resulted in 100% survival. This study highlights the importance of ECM protection for survival during infectious diseases, and paves the way for combined host-pathogen theraphy to fight emerging pathogens.