Abstract 18589: Virus-Derived Serpin Prolongs Survival and Reduces Vasculitis in Lethal Viral Sepsis in Unrelated Infections

Abstract

Lethal viral infections produce a cytokine storm with disseminated vascular leak, clotting, bleeding, organ failure and high mortality, but treatment remains limited. With this cytokine storm there is a massive influx of inflammatory macrophage and T lymphocytes into the arterial wall and affected organs. Serine proteases in clot-forming and clot-dissolving cascades are regulated by inhibitors termed serpins. Serpins such as anti-thrombin III have been used to reduce DIC and improve outcomes but with limited success. Myxomavirus secretes a potent anti-inflammatory serpin, Serp-1, that inhibits thrombotic factor Xa (fXa) and thrombolytic tissue and urokinase-type plasminogen activators (tPA, uPA). Serp-1 treatment was tested in mouse models of lethal gammaHerpesvirus68 and Ebola virus infections. Serp-1 significantly increased survival in both infections, whereas mammalian neuroserpin, that targets only tPA and uPA, did not. Fator Xa levels were reduced in aortic tissues after Serp-1 treatment. Serp-1 reduced virus load, hemorrhage, inflammation, and organ damage. NSP treatment allowed for a marked suppression of normal spleen cell responses during infections on flow cytometry analysis, while Serp-1 did not. RT-PCR array analysis of aortic sections from infected mice demonstrated significantly altered thrombotic and thrombolytic pathway proteases and serpins as well as addressin gene expression changes with Serp-1 treatment but not with NSP treatment. Treatments with other myxomaviral anti-inflammatory proteins, Serp-2 targeting apoptosis, and M-T7 a chemokine modulator showed trends toward reduced inflammation in the MHV68 infected mice. Conclusions: Myxomaviral Serp-1 modulates thrombotic and thrombolytic proteases, markedly improving survival in unrelated lethal viral infections, whereas a mammalian serpin targeting only thrombolysis was ineffective. Treatment targeting both thrombotic and the thrombolytic cascades may improve outcomes in severe viral septic states with vascular inflammation and DIC.