Matrix metalloproteinase-9 deficiency protects mice from severe influenza A viral infection
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
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
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Research Article Infectious disease Pulmonology

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

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

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Figure 13

Mmp-9 deficiency in mice leads to increased survival following H1N1 IAV infection.

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Mmp-9 deficiency in mice leads to increased survival following H1N1 IAV...
H1N1-infected Mmp-9–/– mice are protected from H1N1-induced lung disease and mortality, which may be due their reduced acute lung injury and their more effective adaptive immune response to H1N1 IAV when compared with H1N1-infected WT mice. The reduced lung injury in H1N1-infected Mmp-9–/– mice may be due to reduced lung levels of cytokines and chemokines leading to reduced accumulation of PMNs and macrophages (Mac) in the lung. This, in turn, may reduce the lung burden of deleterious products released by these myeloid leukocytes including oxidants, proteinases, and permogens (such as Tnf-α) that can promote lung injury. Reduced production of Cxc and Ccl chemokines and cytokines by the reduced numbers of myeloid leukocytes may contribute to the blunted recruitment of these cells into the lungs of H1N1-infected Mmp-9–/– mice. H1N1-infected Mmp-9–/– mice also have reduced shedding of the adherens junctional protein, E-cadherin, from lung epithelial cells, and reduced loss of epithelial barrier integrity compared with H1N1-infected WT mice. H1N1-infected Mmp-9–/– mice have an enhanced adaptive immune response characterized by increased numbers of effector cells including cytotoxic NK cells and CD8+ T lymphocytes, and Th1-like CD4+ lymphocytes, along with reduced numbers of antiinflammatory T regulatory cells in their lungs when compared with H1N1-infected WT mice. Soluble E-cadherin is a ligand for the inhibitory receptor, Klrg1, on cytotoxic NK cells and CD8+ lymphocytes, and Th1-like CD4+ lymphocytes. Thus, the lower lung levels of soluble E-cadherin in H1N1-infected Mmp-9–/– mice may also reduce Klrg1 signaling in these adaptive immune cells, and thereby promote their activation and proliferation, and reduce their senescence. Together, these changes likely enhance the adaptive immune system to IAV leading to faster viral clearance, lower lung viral burdens, and improved survival.