Type I interferons induce lung protease responses following respiratory syncytial virus infection via RIG-I-like receptors

The role of proteases in viral infection of the lung is poorly understood. Thus, we examined MMP and cathepsin proteases in respiratory syncytial virus (RSV) infected mouse lungs. RSV induced gene expression for matrix metalloproteinases (MMP) -2, -3, -7, -8, -9, -10, -12, -13, -14, -16, -17, -19, -20, -25, -27, -28 and cathepsins B, C, E, G, H, K, L1, S, W and Z in the airways of FVB/NJ mice. Increased proteases were present in the bronchoalveolar lavage fluid (BALF) and lung tissue during infection. Mitochondrial antiviral-signaling protein (Mavs) and Trif deficient mice were exposed to RSV. Mavs deficient mice had significantly lower expression of airway MMP-2, -3, -7, -8, -9, -10, -12, -13 and -28 and cathepsins C, G, K, S, W and Z. In lung epithelial cells, retinoic acid–inducible gene-1 (RIG-I) was identified as the major RIG-I- like receptor (RLR) required for RSV induced protease expression via MAVS. Overexpression of RIG-I or treatment with IFN-β in these cells induced MMP and cathepsin gene and protein expression. The significance of RIG-1 protease induction was demonstrated by the fact that inhibiting proteases with batimastat, E64 or ribavirin prevented airway hyperresponsiveness and enhanced viral clearance in RSV infected mice.