Matrix metalloproteinase-9 deficiency protects mice from severe influenza A viral infection

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Abstract

Matrix metalloproteinase-9 (MMP-9) cleaves various proteins to regulate inflammatory and injury responses. However, MMP-9’s activities during influenza A viral (IAV) infections are incompletely understood. Herein, plasma MMP-9 levels were increased in patients with pandemic H1N1 and seasonal IAV infections. MMP-9 lung levels were increased and localized to airway epithelial cells and leukocytes in H1N1-infected WT murine lungs. H1N1-infected Mmp-9–/– mice had lower mortality rates, reduced weight loss, lower lung viral titers, and reduced lung injury, along with lower E-cadherin shedding in bronchoalveolar lavage fluid (BALF) samples than WT mice. H1N1-infected Mmp-9–/– mice had an altered immune response to IAV with lower BALF PMN and macrophage counts, higher Th1-like CD4+ and CD8+ T cell subsets, lower T regulatory cell counts, reduced lung type I interferon levels, and higher lung interferon-γ levels. Mmp-9 bone marrow–chimera studies revealed that Mmp-9 deficiency in lung parenchymal cells protected mice from IAV-induced mortality. H1N1-infected Mmp-9–/– lung epithelial cells had lower viral titers than H1N1-infected WT cells in vitro. Thus, H1N1-infected Mmp-9–/– mice are protected from IAV-induced lung disease due to a more effective adaptive immune response to IAV and reduced epithelial barrier injury due partly to reduced E-cadherin shedding. Thus, we believe that MMP-9 is a novel therapeutic target for IAV infections.

Authors

Joselyn Rojas-Quintero, Xiaoyun Wang, Jennifer Tipper, Patrick R. Burkett, Joaquin Zuñiga, Amit R. Ashtekar, Francesca Polverino, Amit Rout, Ilyas Yambayev, Carmen Hernández, Luis Jimenez, Gustavo Ramírez, Kevin S. Harrod, Caroline A. Owen