Abstract 329: Myxomavirus-derived Serpin Prolongs Survival and Reduces Vasculitis in MHV68 Infected Mice by Enhancing IL-10
Background Lethal viral infections produce widespread inflammation with vascular leaking, clotting and bleeding (DIC), and high mortality. Serine proteases in clot-forming (thrombotic) and clot-dissolving (thrombolytic) cascades are activated by a cytokine storm and also induce systemic inflammation. Normal host serine proteases inhibitor (serpin) regulation is lost. Serp-1 is a potent myxomavirus anti-inflammatory protein, which inhibits factor X (fX), tPA and uPA in vitro. Serp-1 reduces arterial inflammation and atherogenesis in many animal models and has been successfully tested in patients with unstable plaque and stent implants.
Methods and results Purified Serp-1 protein treatment significantly improved survival in lethal murine Gammaherpesvirus-68 (MHV68) infection in interferon gamma receptor (IFNγR) knock-out mice (N = 72 mice; P < 0.02) when given for 10 up to 30 days after infection. Treatment with a mammalian serpin, neuroserpin, that inhibits only tPA and uPA, was ineffective (N = 30 mice; P = NS). Serp-1 reduced viral antigen, lung hemorrhage, and aortic, lung and colon inflammation in MHV68 infected mice. Neuroserpin suppressed a wide swath of immune cell responses, while Serp-1 selectively increased CD11c+ splenocytes (macrophage and dendritic cells) and reduced CD11b+ tissue macrophage. Serp-1 significantly increased the IL-10 gene expression in aorta and plasma protein, whereas neuroserpin decreased IL-10. Serp-1 mediated survival in MHV68 infected mice was lost after treatment with IL-10 receptor antibody immediately post infection (N = 12 mice; P =0.014).
Conclusions Serp-1, a unique myxomavirus-deried serpin, improves survival after lethal mouse herpesviral infection, reduces viral load, hemorrhage and arterial inflammation. Serp-1 provides a potential new therapeutic approach for lethal viral sepsis and DIC through altered FX and IL-10.
- © 2013 by American Heart Association, Inc.