**3.5.1 MMPs as modulators of the antiviral immune response**

MMP-9 was one of the first MMPs to be implicated in the mechanism of myocarditis and cardiac dilatation. Heymans et al first showed that inhibition of MMP action through suppression of urokinase-type plasminogen activator, a potent activator of MMPs, and exogenous expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) decreased cardiac inflammation and reduced myocardial necrosis at 7 days, decreasing cardiac fibrosis at 35 days after CVB3 infection (Heymans et al., 2006). When the activity of MMP-2 and -9 were decreased there was a concomitant recovery of cardiac function with decreased immune infiltration. However, shortly after the publication of this paper Cheung et al demonstrated that MMP-9 was in fact a necessary constituent of the antiviral immune response (Cheung et al., 2008). They demonstrated no difference in viral load between MMP-8-/- mice and their WT counterparts. However, MMP-9-/- mice had higher viral loads and virus mediated myocardial damage, during CVB3 infection. Though the antiviral mechanism of MMP-9 action was not explicitly reported, there were significantly elevated levels of interferon-β (IFN-β) in the MMP-9-/- mice. This MMP has been shown previously to cleave and inactivate IFN-β (Nelissen et al., 2003), and IFN-β is known to have a negative feedback effect upon IFN-γ expression (Hanada and Yoshimura, 2002; Yoshimura et al., 2003). The viral loads were similar at early time points (3 – 5 days) post-infection between the genetic MMP-9 knock-outs and WT mice, suggesting that the innate-early immune response was intact, but there were higher viral loads seen in the MMP-9-/- mice 9 days post-infection. These results suggest that there was a deficiency in adaptive immunity in the MMP-9-/- mice, consistent with IFN-β negative feedback inhibition on IFN-γ regulated adaptive immunity in the MMP-9-/- mice.
