Matrix Metalloproteinase 9 Exerts Antiviral Activity against Respiratory Syncytial Virus.

Abdoulaye J Dabo,Edward Eden,Neville Cummins,Patrick Geraghty,John S Tregoning

doi:10.1371/journal.pone.0135970

Abstract

Increased lung levels of matrix metalloproteinase 9 (MMP9) are frequently observed during respiratory syncytial virus (RSV) infection and elevated MMP9 concentrations are associated with severe disease. However little is known of the functional role of MMP9 during lung infection with RSV. To determine whether MMP9 exerted direct antiviral potential, active MMP9 was incubated with RSV, which showed that MMP9 directly prevented RSV infectivity to airway epithelial cells. Using knockout mice the effect of the loss of Mmp9 expression was examined during RSV infection to demonstrate MMP9’s role in viral clearance and disease progression. Seven days following RSV infection, Mmp9 -/- mice displayed substantial weight loss, increased RSV-induced airway hyperresponsiveness (AHR) and reduced clearance of RSV from the lungs compared to wild type mice. Although total bronchoalveolar lavage fluid (BALF) cell counts were similar in both groups, neutrophil recruitment to the lungs during RSV infection was significantly reduced in Mmp9 -/- mice. Reduced neutrophil recruitment coincided with diminished RANTES, IL-1β, SCF, G-CSF expression and p38 phosphorylation. Induction of p38 signaling was required for RANTES and G-CSF expression during RSV infection in airway epithelial cells. Therefore, MMP9 in RSV lung infection significantly enhances neutrophil recruitment, cytokine production and viral clearance while reducing AHR.

Highlights

Matrix metalloproteinase 9 (MMP9) is a zinc-binding endopeptidase that degrades multiple extracellular matrix molecules [1]
Since increased MMP9 levels are observed during an respiratory syncytial virus (RSV) infection [12], we profiled MMP gene and protein expression, and activity in mice on multiple days during RSV infection
This study demonstrates that host expression of MMP9 during RSV infection reduces RSV multiplicity and airway hyperresponsiveness (AHR)

Summary

Introduction

Matrix metalloproteinase 9 (MMP9) is a zinc-binding endopeptidase that degrades multiple extracellular matrix molecules [1]. Persistent MMP9 signaling is associated with tissue remodeling [2] and the progression of many lung diseases including chronic obstructive pulmonary disease (COPD) [2], asthma [3], airway infections [4, 5] and idiopathic pulmonary fibrosis [6]. MMP9 is produced by a range of cells in the respiratory tract and plays several roles in modulating immune responses [7]. MMP9 can activate [8, 9] but inactivate several cytokines and chemokines [1]. MMP9 expression is required for neutrophil migration in an influenza infection mouse model and regulated viral replication [10]. Increased MMP9 levels are detected at the time of respiratory syncytial virus (RSV) infection, a virus frequently

Methods

Results

Conclusion