title: Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality.
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.
authors.affiliation: Department of Biological Regulation, Weizmann Institute, 7610001 Rehovot, Israel; Department of Immunology, Weizmann Institute, 7610001 Rehovot, Israel.
authors.forename: Dalit
authors.initials: D
authors.lastname: Talmi-Frank
authors.affiliation: Department of Immunology, Weizmann Institute, 7610001 Rehovot, Israel.
authors.forename: Zeev
authors.initials: Z
authors.lastname: Altboum
authors.affiliation: Department of Biological Regulation, Weizmann Institute, 7610001 Rehovot, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Solomonov
authors.affiliation: Department of Biological Regulation, Weizmann Institute, 7610001 Rehovot, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Udi
authors.affiliation: Department of Immunology, Weizmann Institute, 7610001 Rehovot, Israel.
authors.forename: Diego Adhemar
authors.initials: DA
authors.lastname: Jaitin
authors.affiliation: Department of Biological Regulation, Weizmann Institute, 7610001 Rehovot, Israel.
authors.forename: Mordehay
authors.initials: M
authors.lastname: Klepfish
authors.affiliation: Department of Immunology, Weizmann Institute, 7610001 Rehovot, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: David
authors.affiliation: Department of Biological Regulation, Weizmann Institute, 7610001 Rehovot, Israel.
authors.forename: Alina
authors.initials: A
authors.lastname: Zhuravlev
authors.affiliation: Department of Immunology, Weizmann Institute, 7610001 Rehovot, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Keren-Shaul
authors.affiliation: Department of Immunology, Weizmann Institute, 7610001 Rehovot, Israel.
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Winter
authors.affiliation: Department of Cell Research and Immunology, Faculty of Life Sciences, Tel Aviv University, 6997801 Tel Aviv, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Gat-Viks
authors.affiliation: National Center for Influenza and Respiratory Viruses in the Central Virology Laboratory at Sheba Medical Center in Tel-Hashomer, 5262000 Ramat-Gan, Israel; Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, 6997801 Tel Aviv, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Mandelboim
authors.affiliation: Faculty of Biology, Technion - Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Ziv
authors.affiliation: Department of Immunology, Weizmann Institute, 7610001 Rehovot, Israel. Electronic address: ido.amit@weizmann.ac.il.
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.affiliation: Department of Biological Regulation, Weizmann Institute, 7610001 Rehovot, Israel. Electronic address: irit.sagi@weizmann.ac.il.
authors.forename: Irit
authors.initials: I
authors.lastname: Sagi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D008168:Lung / Q000473:pathology* / Q000821:virology; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009975:Orthomyxoviridae / Q000254:growth & development*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000473:pathology* / Q000821:virology; D053139:Oseltamivir / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use; D059748:Proteolysis; D020543:Proteome / Q000032:analysis; D040901:Proteomics; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; C507096:Mmp14 protein, mouse; D011480:Protease Inhibitors; D020543:Proteome; D053139:Oseltamivir; D053511:Matrix Metalloproteinase 14
keywords: ECM remodeling; Influenza virus; MT1-MMP; host-pathogen gene regulation; immune genomics; matrix metalloproteinase inhibitors; viral-bacterial coinfection