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JCI Insight. 2018 Dec 20;3(24). pii: 99022. doi: 10.1172/jci.insight.99022. [Epub ahead of print]

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

Author information

1
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, School of Medicine, University of Alabama-Birmingham, Birmingham, Alabama, USA.
3
Laboratory of Immunobiology and Genetics, and Intensive Care Unit, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
4
Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
5
Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Mexico City, Mexico.

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.

KEYWORDS:

Infectious disease; Influenza; Mouse models; Pulmonology

PMID:
30568032
DOI:
10.1172/jci.insight.99022
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